Quick Navigation


Zinc is an essential mineral involved in numerous enzymes. It plays a role in antioxidant enzymes, brain function, and the immune system, among many other biological roles. Zinc is most commonly taken to reduce the frequency of illness and to support optimal levels of testosterone.

Our evidence-based analysis on zinc features 390 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
Last Updated:

Easily stay on top of the latest nutrition research

Become an Examine Member to get access to all of the latest nutrition research:

  • Unlock information on 400+ supplements and 600+ health topics.
  • Get a monthly report summarizing studies in the health categories that matter specifically to you.
  • Access detailed breakdowns of the most important scientific studies.

Try FREE for 14 days

Research Breakdown on Zinc

1Sources and Biological Significance

1.1Source and Origin

Zinc is an essential mineral found in high levels in animal tissues and eggs, legumes, and fish; it is exceptionally high in shellfish such as oyster[3][4] and may also be fortified into cereal grains in developed countries.[5]

Zinc is most commonly touted to be important as it is a cofacter in over 300 enzymes involved in gene expression, cell proliferation and signal transduction[6][7][8] and deficiencies of zinc may reduce the activity of these enzymes.

1.2Biological Significance

Zinc's main role in the body is as a prosthetic group for several enzymes called metalloproteins, one of which is the Superoxide Dismustase enzyme; an endogenous anti-oxidant involving both zinc and copper.[9][10][11] Zinc is also involved in regulating the immune system.[12][13]

1.3Intake and Requirements

The RDA values for zinc are an Estimated Average Requirement (EAR) of 6.5mg for females, 8.5-10mg for pregnant or lactating females, and 12mg a day for men. The Recommended Daily Intake (RDI) values are 8mg for females, 10-12mg for pregnant or lactating females, and 14-15mg for males, and the Tolerable Upper intake Limit (TUL) is in the range of 35-40mg for adults of both genders (all numbers daily requirements).[14][15]

1.4Zinc Status and Deficiency

A deficiency in zinc is related to delayed growth in youth and hypogonadism in adult males[16] as well as general mental lethargy and skin abnormalities.[17]

Zinc deficiency is mostly associated with cognitive deficits (memory and mood) as well as growth impairments in youth

When looking at zinc deficiency rates, it has been noted that around 10% of persons (USA) have a dietary intake of less than half the RDA of zinc[18][19] while global deficiency rates are over 50% (due to high deficiency rates in third world countries).[19] It has been reported (WHO, 2002) to be a major factor contributing to 1.4% deaths worldwide associated with severe zinc deficiency in childhood[20] although this magnitude of deficiency is almost never observed in first-world countries.[21]

In general, while zinc deficiency does seem to be an issue the overall rates of zinc deficiency are significantly less than other vitamins or minerals of concern (such as Vitamin D) and it is wholly possible to consume enough zinc via the diet

Zinc is lost during sweat and exercise[22][23] and may be a contributing factor to why testosterone levels seem to be depressed after exhaustive exercise.[24][25]

Excessive sweating over a prolonged period of time (seen in athletes) may predispose athletes to zinc deficiencies

In diabetic individuals (following information seems to apply equally to type I and type II diabetics), urinary zinc excretion rates are increased[26][27][28] and although serum zinc concentrations are unreliably influenced (increased,[26][29] decreased,[30][31][32] or not different from non-diabetic controls[33]) cellular concentrations of zinc as measured in immune cells (mononuclear cells, granulocytes, lymphocytes and leucocytes) tend to be reduced relative to nondiabetic controls.[30][34][31]

Diabetics (both type I and type II) appear to be at higher risk for zinc deficiencies than do non-diabetic persons

1.5Formulations and Variants

Zinc Citrate, at 50mg elemental Zinc (146mg) daily for 4 weeks is associated with a maintenance of Zinc status while placebo declines over time (told to maintain a low Zinc diet, estimated between 10-12mg).[35]

Zinc Gluconate, at 50mg elemental Zinc (385mg), appears to be slightly more effective than Zinc Citrate (nonsignificant) and can increase serum and erythrocytic stores of Zinc in apparently healthy persons over a period of 4 weeks.[35]

Zinc Picolinate (bound to picolinic acid, a metabolite of tryptophan), at 50mg elemental Zinc (144mg) in healthy persons appears to increase urinary and serum levels greater than placebo and the other two forms tested (Citrate, Gluconate).[35]

Zinc carnosine (ZnC) is a synthetic molecule where zinc and carnosine are linked together in a 1:1 ratio, forming a polymer-structure. The compound has been used for some time in Japan as a treatment for gastritis and gastric ulcers, and studies have shown that ZnC is up to 3 times more effective at promoting gastric integrity than either zinc or carnosine alone.[36] When the integrity of gastrointestinal (GI) tract becomes compromised, intestinal permeability increases which may allow the passage of harmful substances into the blood stream. This can cause an immune response, leading to systemic inflammation. Although not an official medical term, conditions associated with increased intestinal permeability have been termed ‘leaky gut’ syndrome, which can be caused by food allergies, certain medications and inflammatory bowel disease.[37]

While ZnC is known to protect against increases in intestinal permeability, the mechanisms at work are not entirely clear. One study employed several in vitro and in vivo models to examine the mechanisms behind ZnC protection of the GI tract.[38] To examine the effects of ZnC on wound healing mechanisms that may be important in the context of leaky gut syndrome, HT129 colonic cells were grown to form a cell monolayer covering the entire surface cell culture plates. An artificial ‘wound’ was then induced by scraping a line through the entire cell monolayer, removing all cells within the scratch. The ability of the cells to migrate back into the scratch, ‘healing’ the cell monolayer was then tested in the presence or absence of ZnC. ZnC increased cell migration by approximately 100% compared to the vehicle control, suggesting that it may promote gastric healing in part by increasing epithelial cell migration in injured regions of the GI tract.[38] ZnC also induced a dose-dependent increase on cell proliferation, with a maximal response at 100μM.[38]

ZnC increased the migration and proliferation colonic epithelial cells in vitro, suggesting that it may promote gastric healing in part by interacting with epithelial cells lining the GI tract.

To examine the ability of ZnC to promote gastric healing in vivo, researchers also examined the effects of ZnC in a rat model for gastric damage. Rats were given ZnC (1 or 5 mg/mL) or a placebo prior to 20 mg/kg indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that causes gastric damage. ZnC substantially decreased markers for gastric damage at both 1 and 5 mg/ml, with the 5 mg/ml dose being more effective.[38]

The ability of ZnC to prevent small intestinal damage by indomethacin was also evaluated in mice. In control mice that received indomethacin alone, substantial shortening of intestinal villi were noted, along with decreased intestinal weight, both indicators of damage. In contrast, ZnC treatment reduced indomethacin-induced villus-shortening and increased intestinal weight, indicating a protective effect.

ZnC has demonstrated significant protective effects in animal models of NSAID- induced GI injury.

To validate the results obtained with in vitro cell culture studies and animal models, 10 healthy human volunteers were recruited in a double-blind, randomized and placebo controlled study. To assess the effects of ZnC on indomethacin-induced increases in intestinal permeability, participants drank a sugar solution containing a mixture of mono-and disaccharides. Since disaccharides are larger and are not easily absorbed in the GI tract by passive diffusion, an increase in urine disaccharide to monosaccharide ratio indicates increased intestinal permeability due to damage. Subjects took either ZnC (37.5 mg twice daily) or a placebo for seven days, with indomethacin for the last 5 days. When taking a placebo, subjects showed a 3x increase in disaccharide ratio, indicating a substantial increase in intestinal permeability from the indomethacin-induced injury. In contrast, subjects taking ZnC showed no significant increase in disaccharide ratio, indicating a strong protective effect on the gut mucosa.[38] 

ZnC has been shown to prevent increased intestinal permeability from NSAID-induced injury in humans. Evidence for this effect is strong, having been demonstrated in a randomized, double blinded and placebo controlled trial with a crossover design. The effective dose of ZnC in this study (37.5 mg twice/day) is easily achievable with over the counter supplements.



The regulation of bodily zinc levels tends to occur at the level of the intestines secondary to regulated absorption and fecal excretion[39][40] and in instances of zinc deficiency intestinal absorption can near 100%.[39] This has been replicated in humans where zinc absorption during instances of deficiency and is attenuated with sufficiency.[41][42][43]

At least one animal study has suggested that dysregulation occurs with intestinal zinc absorption during aging, and adequate dietary intake may in turn be metabolically insufficient due to poorer absorption.[44]

Absorption of zinc tends to be regulated, with higher oral intakes being associated with lower bioavailability and approximately 5mg absorbed in postmenopausal women regardless of dietary or supplemental intake.[45]

2.2Transportation in Serum

In otherwise healthy men supplemented with zinc, fasting plasma concentrations can increase within five days of supplementation regardless of baseline zinc status.[46] 10mg and 20mg elemental zinc (syrup) were equivalent in their ability to heighten plasma zinc levels, and were normalized two weeks after zinc supplementation.[46]

2.3Neurological Distribution

Zinc, as a trace mineral, is present in the cerebral cortex, pineal gland, and hippocampus where it acts as an atypical neuromodulator.[47][48][49] In the hippocampus, particularly the vesicles of mossy fibers, zinc can reach concentrations of 220-300μM which is around 8% of total brain zinc[50] (concentrations of free zinc are more modest at 1-20μM[51][52]) and is sensitive to prolonged (but not acute) zinc deficiency,[53] while in the pineal gland it may regulate the response of this organ to leptin.[54]

Similar to most neuromodulators, zinc is released from the synapse upon action potentials.[55]

Zinc is an endogenous neuromodulator that is present in high concentrations in the hippocampus and pineal gland, and is released from the synapse upon actions potentials

2.4Cellular Kinetics

The cell can take up zinc via ion channels such as the AMPK/kainate calcium channel (in neurons)[56] where it is then taken up by the cell's mitochondria.[56][57]


3.1Glutaminergic Neurotransmission

The zinc ion has been noted to possess moderate potency NMDA receptor inhibitory actions in the range of 100-1,000µM without affecting basal currents, while the activity of 10µM was weak and the IC50 value placed near 100µM;[58] the effects on NMDA receptor agonists appeared to be similar to magnesium.[58]

Zinc may also activate neuronal potassium channels and reduce glutamate release into the synapse.[59]

Zinc ions appear to be antiglutaminergic modulators, able to reduce the release of glutamate and its signalling through glutaminergic receptors. The concentration which does this is rather high, however, and this may not be physiologically relevant to zinc

3.2Serotonergic Neurotransmission

In the corpus callosum (commissure between brain hemispheres, function appears to be altered in depression[60][61] and serotonin uptake may be hindered by antidepressants fluoxetine and imipramine[62]), elemental zinc and zinc sulfate can enhance uptake at a relevant concentration of 1µM by 45%.[63] This increase in uptake was also noted the cingulate cortex (58%) and Raphe nucleus (65%), concentrations of zinc between 10-100nM were ineffective, and the hindering effects of antidepressants on this function was negated with 1µM zinc.[63]

Zinc appears to be involved in increasing serotonin uptake in select brain regions, and due to the concentration required for this effect it may be physiologically relevant. It appears that some antidepressants may reduce serotonin uptake in these brain regions if zinc concentrations are too low


Brain-derived neurotrophic factor (BDNF) is a protein found in both serum and brain (serum concentrations thought to be reflective of brain concentrations[64]) which is involved in regulating neuronal growth and plasticity;[65] BDNF signalling is implicated in both depression and memory function.[66] Zinc is known to be involved with BDNF as a deficiency of zinc seems to reduce the ability of BDNF in activating its receptors[67] and zinc itself can form a complex with the BDNF protein,[68] although it is primarily thought that via activating some metalloprotein enzymes (MMP-2 and MMP-9) which has been noted with oral zinc in mice[69] that zinc helps cleave the inactive form of BDNF (pro-BDNF) into 'mature' or active BDNF.[70]

High levels of dietary zinc in mice (30ppm via diet with 60ppm via supplemented drinking water) has been noted to reduce the actions of BDNF in the brain and impair memory, which was noted to be associated with a zinc deficiency in the hippocampus.[71] Zinc injections directly increase BDNF,[71] and the reason why high oral intake led to a reduction in hippocampal zinc is not known.

The antidepressive effects of zinc are thought to be mediated by an increase in BDNF, which has been noted in the serum of depressed humans given 30mg elemental zinc over the course of 12 weeks compared to placebo.[72] This study noted that baseline BDNF in serum, 15.37+/-8.28ng/mL, was increased 42% to reach 21.84+/-6.87ng/mL despite no change in placebo and this occurred alongside a 41% increase in serum zinc concentrations.[72]

Such an increase in BDNF has failed to occur elsewhere when 25mg was given as adjuvant over the same time length to depressed persons already on SSRI therapy despite zinc bettering symptoms of depression.[73]

Zinc has been noted to increase serum BDNF levels, with the magnitude of increase correlating highly with increases in serum zinc


Despite its importance in the brain, high concentrations of zinc can be excitotoxic[74] and this is sometimes seen in ischemic injury where an excess amount of zinc is released from the synapse and mediates cell death[74][75] and infarctions.[76] This is why zinc chelators are therapeutic in instances of stroke rehabilitation.[77]

Although likely not reflective of supplementation (unless abnormally high doses of zinc are ingested), zinc may be a mediator of cell death when ischemia or hypoxia occur

3.5Addiction and Obsession

Obsessive compulsive disorder is known to at least be associated with glutaminergic abnormalities, particular an excessive level of synaptic glutamate and signalling thereof[78][79] which positively correlates with symptom severity.[80] As glutamate antagonists have been previously implicated in treating OCD[81] and zinc has the potential to be anti-glutaminergic, it is investigated for possible benefits.

The addition of zinc (220mg twice daily) to fluoxetine therapy (20mg) for obsessive compulsive disorder is able to reduce symptoms of OCD as assessed by the Y-BOCS rating scale, although the benefits were present at weeks two and eight but not 4-6.[82]

3.6Appetite and Food Intake

A deficiency of zinc is known to be a cause of anorexia (reduction of appetite, not the same as anorexia nervosa), and is usually the first symptom of a zinc deficiency[83] and is shortly followed by depressive symptoms and anhedonia.[84]

Zinc deficiencies are known to reduce appetite, and this is usually the first symptom of a zinc deficiency

In rats, orally supplemented zinc (19mcg/kg) appears to stimulate food intake and this effect was not observed with other bivalent cations.[85] Injections of zinc seem ineffective,[85] even in deficient rats.[86]

Oral zinc appears to stimulate the vagal nerve (effects abolished by vagotomy[85]) which then increase mRNA translation of the two appetite stimulating neural factors orexin and neuropeptide Y (also abolished by antagonists of these receptors[85]). Zinc is known to activate the GPR39 receptor (a Ghrelin receptor)[87] and since ghrelin is known to stimulate these two neural fators via the vagus nerve[88][89] it is thought that this receptor is the molecular target of zinc.

Zinc appears to positively influence appetite in rats who are not zinc deficient, and this may be related to activating a receptor (GPR39) that is involved in ghrelin signalling

3.7Attention and Focus

In children with ADHD, 30mg elemental zinc daily for 13 weeks (final five weeks used alongside D-amphetamine) was able to reduce the amount of D-amphetamine that was needed by 37% and reduced affective blunting from 21% (placebo with amphetamine) to 11%; however, zinc supplementation inherently failed to benefit symptoms of ADHD.[90]

While zinc at 30mg elemental zinc appears to be slightly effective as an addition to D-amphetamine therapy, it does not appear to inhernetly have a significant therapeutic benefit


Depressed patients appear to have reduced circulating zinc concentrations in serum[91] which is further reduced in treatment resistant persons relative to treatment non-resistant (treatment being imipramine)[92] and the magnitude of zinc deficiency correlating with severity of depression.[93][94] Overall, persons with depression seem to usually have lower zinc concentrations in serum and the worse the symptoms of depression the lower the zinc concentration tends to be.

At least in rats, the depressive[95] and behavioural symptoms (increased susceptability to stress[96]) that are seen with two weeks of zinc deprivation are normalized upon supplemetnation of zinc. Interestingly, deprivation of zinc causes rats to be resistant to fluoxetine (SSRI) therapy.[95]

In patients with major depression given zinc therapy (25mg elemental zinc) alongside their antidepressant medication (SSRIs) noted that supplementation had an adjuvant role by reducing depressive symptoms over 12 weeks when compared to SSRI paired with placebo;[73] monotherapy alone at 30mg elemental zinc in overweight/obese depressed persons appears to also reduce depressive symptoms (assessed by BDI II) over 12 weeks when compared to placebo.[72]

Serum zinc concentrations and zinc status are negatively correlated with the risk of developing depression, and in persons who are depressed zinc status is further negatively correlated with the severity of depression. Supplementation of zinc at 25mg (elemental) or higher has preliminary evidence for working in humans either as adjuvant therapy with SSRIs or inherently

Zinc has been reported to noncompetitively inhibit glycogen synthase kinase-3β (GSK3β) with an IC50 of 15µM.[97] As GSK3β is a molecular target of mood disorders[98] and mood disorders being associated with alterations in zinc metabolism[99] supplementation is thought to have a potential role in its treatment.[18]

Zinc is an endogenous inhibitor of glycogen synthase kinase-3β, which is involved in mood disorders and depression. This is thought to be the molecular target for zinc and its interactions with mood and depression

In otherwise healthy young women given 7mg of elemental zinc in a multivitamin format (placebo given the same multivitamin), depressive and aggressive symptoms were modestly but significantly reduced relative to placebo.[100] This modest benefit to mood has failed to occur in healthy elderly perosns (70-87yrs) given 15-30mg zinc as assessed by POMS.[101]

In persons given imipramine but were resistant to treatment, supplementation of 25mg elemental zinc for twelve weeks is able to reduce depressive symptoms relative to placebo to the levels seen with non-resistant persons as assessed by BDI, HAMD, and CGI.[102]

Zinc appears to be notably effective in treatment resistant depression alongside other pharmaceuticals, although it does not seem to inhernetly have an effect in depression that is responsive to treatment. The per se antidepressant effects of zinc supplementation in persons without treated depression are modest at best

3.9Memory and Learning

Zinc is known to be highly concentrated in the hippocampus[47][50] and a deficiency of zinc is associated with both mood disorders as well as impaired memory formation.[103] While a dietary insufficiency of zinc is known to cause a corresponding decrease in hippocampal zinc (attenuated with supplemental zinc[103]), high oral intakes in mice (additional 60ppm to drinking water) have also been noted to paradoxically reduce zinc concentrations in the hippocampus[71] which is not seem with mild elevations in rats (10ppm).[104]

The negative effects of low zinc concentrations in the hippocampus seem to be related to spatial memory,[103] and spatial memory is known to be associated with brain-derived neurotrophic factor (BDNF) signalling;[105] accordingly, injections of zinc into the rat brain cause dose-dependent increases in BDNF signalling and protein content[71] and a deficiency results in decreased BDNF signalling although the elevated protein content suggests insensitivity of the TrkB receptor.[67]

Zinc deficiency is associated with impaired memory formation and impaired signalling of the BDNF growth factor, and improving zinc status is associated with betterment on both accounts. An abnormally high zinc intake is also associated with memory impairment, and oddly it is associated with a reduction rather than surplus of zinc in the brain

In general and in studies on how zinc influences spatial memory formation, low dose zinc in drinking water (10ppm) has been associated with beneficial,[69][106] adverse,[104] and no significant alterations.[71] Greater elevations (60ppm) have been noted to force a reduction in spatial learning associated with reduced hippocampal zinc and BDNF,[71] although at least one study noted impairments in memory at 10ppm alongside an increase in brain zinc concentrations.[104] This negative effect of zinc on spatial memory has been noted in one rat study to be significantly reduced with coadministration of copper (at approximately 2.5% the dose of zinc).[107]

There is mixed evidence for whether zinc higher than the standard dietary intake is beneficial or negative for spatial memory formation, although at least one study noted that low dose copper exerted a protective effect against zinc (in a study where zinc had a negative effect)

In persons who experienced subacute stroke and had suboptimal dietary intake of zinc (6.6mg or less), supplementation of 10mg elemental zinc was associated with greater improvements than placebo on cognition as assessed by the NIH stroke scale after 30 days.[108]

In persons who suffered from stroke and have inadequate dietary intake, cognitive improvements following stroke appear to be accelerated relative to placebo

4Cardiovascular Health


Zinc is thought to be an anti-atherogenic agent[109] and in particular a zinc deficiency is thought to be a risk factor for atherogenesis with supplementation alleviating this risk.[110] Dietary zinc intake is known to be inversely associated with atherosclerotic buildup in arteries.[111]

In otherwise healthy elderly persons (higher risk of zinc deficiency), supplementation of 45mg elemental zinc daily (as gluconate) daily for six months is associated with reductions in cell adhesion factors (ICAM-1 and vCAM-1) and inflammatory cytokines including C-reactive protein, IL-6, and MCP-1.[112]

Normalizing a zinc deficiency appears to be assoiated with a reduced risk for arterial plaque buildup (atherosclerosis)

4.2Lipoproteins and Triglycerides

Supplementation of 20mg elemental zinc in obese insulin resistant children over eight weeks is associated with a reduction in total cholesterol and LDL-C.[113]

Oxidized LDL-C appears to be reduced when insulin resistant children are given 20mg elemental zinc for eight weeks, possibly secondary to reducing the state of insulin resistance.[113]

5Interactions with Glucose Metabolism


20µM zinc has been noted to, in vitro in liver cells, to increase the activity of glycogen synthase 2-fold secondary to its inhibition of GSK-3β (IC50 15µM).[97]

Due to inhibiting GSK-3β, zinc can increase the activity of glycogen synthesis


Zinc has been reported to act via the insulin receptor[114] and phosphorylate Akt in vitro, which is downstream of the insulin receptor.[31] The inhibition of glycogen synthase kinase-3β (GSK3β) that occurs with zinc[97] is able to preserve insulin signalling, as GSK3 is a negative regulator of insulin signalling via IRS-1.[115] Zinc can augment uptake of glucose into cells that express insulin-sensitive GLUT4, but not other GLUT transporters.[97]

Zinc may positively influence insulin signalling via preventing a negative regulator (GSK3β) from suppressing insulin signalling. This seems to occur at low enough concentrations that it is physiologically relevant


In diabetic individuals (following information seems to apply equally to type I and type II diabetics), urinary zinc excretion rates are increased[26][27][28] and although serum zinc concentrations are unreliably influenced (increased,[26][29] decreased,[30][31][32] or not different from non-diabetic controls[33]) cellular concentrations of zinc as measured in immune cells (mononuclear cells, granulocytes, lymphocytes and leucocytes) tend to be reduced relative to nondiabetic controls.[30][34][31]

Beyond measuring zinc concentrations themselves (as serum markers are not thought to be overly reliable for subclinical deficiencies[116]), a sensitive biomarker for zinc deficiency (Ecto 5' nucleotidase[117]) is also known to be reduced in diabetic persons relative to control.[118]

Three weeks of supplementation with 30mg elemental zinc (glycine chelation) appears to be sufficient to at least partially restore a zinc deficiency in diabetics.[118]

Although somewhat unreliable in plasma measurements, it is more likely than not that persons with diabetes (both type I and type II) are at an increased risk for zinc deficiency which can be remedied fairly rapidly with zinc supplementation

In obese insulin resistant children (who were likely deficient in zinc) given 20mg elemental zinc for eight weeks supplementation was associated with a betterment of all biomarkers of glucose metabolism including blood glucose (7% reduction), fasting insulin (23% reduction), and insulin sensitivity as assessed by HOMA-IR (31% improvement)[113] which has been reported elsewhere in a replication.[119]

In diabetics who have been confirmed to have adequate stores of zinc, further supplementation of high dose zinc (240mg elemental zinc as gluconate) for three months has failed to have any appreciable benefit.[120]

In diabetics or insulin resistant persons who are deficient in zinc can help normalize parameters of glucose metabolism including glucose, insulin, and sensitivity to insulin; if the same persons are already sufficient in zinc, further supplementation has no additional benefit

6Immunology and Inflammation

6.1Tumor Necrosis Factor

Tumor necrosis factor alpha (TNF-α) is a cytokine that is reduced in states of zinc deficiency (restored upon zinc replenishment[121]).

Ex vivo production of TNF from macrophages in elderly persons who supplemented 45mg elemental zinc for a year appears to be reduced.[122]


IL-2 is known to be decreased with zinc deficiency[121] and restored upon replenishment.[121]

Ex vivo production of IL-2 (assessed by the induction of IL-2 mRNA from stimulated immune cells) is increased with supplementation of zinc at 45mg for a year, despite basal concentrations of IL-2 being unaffected.[122]


Zinc deficiency is known to lead to a reduced count of T-cells and subsequently depressed humoral and cell-mediated immunity.[123]

300 mg of zinc sulfate daily for 6 weeks impaired lymphocyte stimulation by t-cells in response to phytohemagglutinin. Chemotaxis and phagocytosis from polymorphonuclear leukocytes were considerably lower, suggesting greater susceptibility to infection. This is many times the normal supplemental intake and RDA.[124]

6.4Rhinovirus and URTIs

Rhinovirus is known as the common cold, and URTI is the acronym for 'Upper respitatory tract infection'

A meta-analysis of 15 trials including 1360 persons overall noted that zinc, in the form of lozenges (gluconate) or syrup (sulfate), was associated with less duration and severity of the common cold when taken within 24 hours of onset that, after a week, had an odds ratio of 0.45 (less than half the risk).[125]

High dose zinc in response to the common cold (not taken preventatively, but only at the onset of sickness) appears to be effective in reducing the duration and severity of sickness

Supplementation of 45mg zinc in elderly persons (with lower zinc concentrations in serum relative to young controls) for a year is associated with a reduced rate of upper respiratory tract infections (50% reduction that failed to be significant) and general infections (88% occurrence reduced to 29%).[122]

Prolonged supplementation of zinc over five months is associated with a reduced incidence of sickness (RR 0.64) although with a high variability.[125]

Supplementation of zinc daily as a preventative appears to reduce the rate of getting colds


In children with acute pneumonia, 10-20mg elemental zinc (as acetate syrup) over two weeks failed to outperform placebo in reducing the length of sickness.[126]

In studies where zinc is used by itself (monotherapy) in response to pneumonia, it seems to usually fail to outperform placebo

Supplementation of zinc at 20mg as adjuvant therapy (alongside antibiotics) was effective in further reducing recovery time in children under two years old with very severe pneumonia, but due to having no effect in severe pneumonia and the benefit in very severe being lost when controlling for underweight children the authors concluded no significant overall effect of treatment.[127] Other studies using the same dose that differentiate between severe and nonsevere pneumonia note a failure of zinc therapy outright relative to placebo[128][129][130] or that the beneficial effects were insignificant (statistically and clinically).[131] Although most evidence suggests a lack of efficacy, there is some counter evidence with the same protocol noting efficacy in reducing the length of sickness for severe pneumonia[132] and a study that noted a failure overall with zinc supplementation did report reduced mortality with severe pneumonia (which mostly protected children with HIV).[130]

When zinc is used as an adjuvant (alongside another drug, with the placebo group given the drug in isolation), it still appears to be mostly ineffective against pneumonia

The usage of zinc as a preventative for two weeks (10-20mg elemental zinc daily) was unable to influence the occurrence of pneumonia in children measured over the following six months.[133]

Limited evidence on the usage of zinc as preventative for pneumonia has failed to find a protective effect


Adults with diagnosed HIV appear to be at greater relative risk for zinc deficiencies at up to 50%[134][135][136] and those who are deficient seem to have faster disease progression[137][138] and mortality;[139] a dietary surplus of zinc also appears to be associated with negative effects in this cohort, specifically an increased disease progression rate to AIDS.[140]

In HIV positive adults with confirmed low plasma zinc concentrations (0.75μg/mL or less) given 12-15mg elemental zinc daily for 18 months, zinc supplementation was associated with a four-fold reduced risk of immunological failure relative to placebo without affecting viral load[141] and has elsewhere been associated with significantly less opportunistic infections regardless of whether or not subjects were on antiretroviral therapy.[142]

In children diagnosed with HIV who also experience severe pneumonia, supplementation of zinc appears to be effective in reducing mortality (7 deaths in control and none noted with zinc at 20mg daily for seven days).[130]

Zinc appears to be more likely to be deficient in persons with HIV, and while low doses are seen as protective higher doses exceeding the tolerable upper limit (TUL) might also be adverse. It is recommended to low-ball zinc supplementation at 10-15mg elemental zinc

Zinc inhibits 3C-like protease and papain-like protease 2, enzymes essential to the function of severe acute respiratory syndrome-coronavirus (SARS-CoV), in vitro. It is not known to what degree zinc status is relevant to the risk of infection or how zinc availability in vivo would impact the virus.[143][144]

7Interactions with Oxidation


In a study dividing athletes and sedentary persons into a zinc supplement (5mg/kg zinc sulfate daily), both athletic and sedentary persons given zinc experienced a reduction in levels of lipid peroxidation relative to placebo and an increase in levels of the enzymes glutathione peroxidase and SOD.[145]

8Interactions with Hormones


Bodily zinc stores are positively associated with serum testosterone[146][147] and increased urinary excretion negatively associated (as well as magnesium).[148]

Zinc deficiency is also associated with an impairment of converting cholesterol and lipid precursors into sex hormones despite testicular cell uptake being unaffected[149] and other side-effects associated with zinc deficiency include the population of androgen receptors being reduced overall (59% of control)[150] and in male sex organs (36% of control);[151] this may be related to how the androgen receptors have a zinc binding site,[152] and their functionality is impaired without adequate zinc.

A zinc deficiency can reduce the expression of androgen receptors and the synthesis of testosterone in cells, both of which reduce the overall effects of testosterone

When looking at rat studies that are not models of deficiency, zinc supplementation is able to increase circulating testosterone and free testosterone when injected at 3mg/kg[153] and oral intake of 20mg/kg zinc chloride has increased testosterone to levels higher than baseline in rats.[154]

Some animal research suggests that high doses of zinc (or moderate doses of injections) can increase circulating testosterone concentrations

In human studies of zinc deficiency supplementation of zinc is able to increase circulating testosterone concentrations, with this study noting that 250mg zinc sulfate for six weeks is able to increase testosterone by 84% (1.55nM/dL to 2.96nM/dL) in persons on hemodialysis.[155]

Infertile men who also have low testosterone (less than 4.8ng/mL) experience an increase in testosterone following zinc supplementation, but this is not observed in men with normal testosterone levels.[156]

In human instances of zinc deficiency, relatively modest supplemental dosages appear to be able to increase circulating testosterone concentrations

Supplementation of ZMA in persons with an adequate zinc intake in the diet (11.9-23.2mg) failed to significantly increase circulating testosterone or free testosterone[1] and this failure to increase basal testosterone concentrations is also seen with 15mg elemental zinc in cyclists[157] and 3mg/kg zinc sulfate in elite wrestlers.[158]

When measuring testosterone acutely following exercise, there is a slight increase in free testosterone associated with zinc supplementation at 15mg in men who are not otherwise deficient[157] and the decrease in testosterone and free testosterone that may occur with exhaustive exercise is attenuated with zinc sulphate supplementation at 3mg/kg in elite wrestlers[158] and in sedentary men subject to cycling.[159]

In men who are not deficient in zinc, there can be a preservation (not necessarily increase) in zinc concentrations when combined with strenous exercise. If exercise is not a factor, then zinc doesn't appear to have any influence on testosterone

8.2Dehydrotestosterone (DHT)

Zinc is thought to reduce DHT secondary to inhibition of 5α-reductase (converts testosterone to DHT) in the 3-15mM range (up to 98% inhibition), although concentrations as low as 500µM are minimially effective (30%).[160] It is synergistic with vitamin B6 in this regard despite B6 not possessing any inherent inhibitory properties, which may explain the formulation of ZMA.

Injections of 10-20mg zinc (gluconate and arginine included in the weights here) into the prostate of rats has noted inhibitory effects on 5α-reductase (50.48% at 20mg)[161] although a study in human prostate tissue in vitro noted that low concentrations (300nM) increased activity of this enzyme while higher concentrations (3mM) were potently inhibitory.[162]

When looking at the subdivisions of 5α-reductase, the type I variant is effectively inhibited in skin cells with an IC50 of 2µM while it is fairly ineffective on type II[163] and in these tissues it is still synergistic with B6.[160]

Zinc appears to be a 5α-reductase inhibitor, and in vitro appears to be fairly potent. It is not sure if this is relevant following oral supplementation though, since low concentrations actually increase enzyme activity (with higher concentrations being potent in inhibiting the enzyme) and these high concentrations may not occur in the body

In infertile men, regardless of whether circulating testosterone was above or below the predetermined threshold (4.8ng/mL) supplemental zinc was able to increase circulating concentrations of DHT.[156]

In infertile men, an increase in DHT is noted which suggests that the lower concentration of zinc (which increases the activity of the 5α-reductase enzyme) is more relevant


A zinc deficiency in rats is associated with an increased expression of estrogen receptors (57%)[150]

8.4Insulin-like Growth Factors

IGF-1[164][118] and IGFBP3[164] are reduced in persons experiencing a dietary zinc deficiency, which is normalized upon supplementation.

An increase in IGF-1 has been noted in elderly persons given 30mg zinc supplementation daily for four weeks, where the 22.4+/-4.7% increase seen with a whey protein supplement was boosted to 48.2+/-14%.[165]


Leptin is known to interact with zinc at the level of the pineal gland[54] and may mediate its actions.[166] A zinc deficiency is known to reduce leptin production and secretion from adipocytes[167] which has been detected in rats[168] and humans.[121]

A zinc deficiency is associated with reduced production and secretion of leptin

Leptin secretion can be positively influenced by insulin[169] although as zinc repletion does not influence insulin[121] this is not thought to be a mechanism of action. TNF-α and interleukin-2 (IL-2) have both been found to be increased when a zinc deficient person has their zinc status restored[121] and these factors are known to induce leptin expression.[170] IL-2 itself is zinc dependent,[171] and it is thought that the influence on leptin couldl also be indirect via these two molecules.

The interaction of zinc and leptin may have other proteins (TNF-α and interleukin-2) as mediators

In men with marginal zinc deficiency (restricted to about 5mg daily for 4+/-2 months), supplementation of 30-60mg elemental zinc (as acetate) daily for 6-12 weeks is associated with a 64% increase in leptin relative to the deficient state.[121]

Supplementation of zinc to a deficient person is able to increase circulating leptin concentrations

9Interactions with Organ Systems

9.1Tongue and Mouth

Reductions in taste acuity are among the first noticeable signs of zinc deficiency, usually alongside anorexia (loss of appetite) and impairment in cognition.[172] This is likely because of a zinc-dependent enzyme, gustin, being reduced in activity when salivary zinc is low[173] and this condition is easily treated with supplemental zinc.[174]

Adolescents given zinc supplements over the course of ten weeks have been noted to experience increases in taste acuity as assessed by recognition thresholds for salt was improved;[175] these subjects (adolescent girls in India) usually have zinc deficiency rates around 58.3-65%[176][177] and thus the observed effects could be from normalizing a deficiency.

Zinc deficiency is associated with impaired taste, and supplementation of zinc is able to enhance taste acuity when it is normalizing a deficiency

Loss of taste associated with chemotherapy does not appear to be rehabilitated with supplementation of 220mg zinc sulfate (50mg elemental zinc) twice daily.[178]

Taste losses (hypogeusia) associated with chemotherapy does not appear to be influenced with oral zinc supplementation, while altered perception of taste (dysgeusia) has mixed evidence (covered in the cancer section)

In low socioeconomic children at risk for zinc deficiency, 15mg elemental zinc daily for ten weeks is associated with reduced plaque formation on teeth.[179]

May reduce dental caries, if normalizing a zinc deficiency; limited evidence


Zinc chloride appears to be capable of preventing secretagogue-induced acid secretion in rat and human stomach tissue,[180] which although therapeutic for the stomach may limit its own subsequent absorption.[181]


Trace minerals appear to be altered in their concentrations in the cirrhotic liver and serum, with a known decrease in zinc[182][183] and increase in copper[183][184] relative to healthy controls; the deficiency in zinc appears to positively correlate with disease progression.[185]

In persons with liver cirrhosis, supplementation of 50mg elemental zinc (as sulfate) daily for 90 days is associated with improvements in cirrhotic state as assessed by Child-Pugh score (6.56 down to 5.72; 13% improvement) which was associated with less bodily copper levels.[186]

Supplementation of zinc may be slightly therapeutic in instances of liver cirrhosis


Very high levels of zinc intake (330mg daily) has been implicated in alleviating leaky gut syndrome in those with Crohn's Disease.[187] It can also prevent or alleviate damage to the intestinal mucosa and some to the liver done by alcohol[188][189][190] and due to alcohol causing zinc depletion, can also provide therapeutic-like benefit in treating alcohol-induced damage to the gut and liver.[191][192] Many of these effects were noted as dose dependent, but were seen at 3-5mg/kg bodyweight (an incredibly high dose).


Zinc deficiency is associated with impaired hearing in mice and rats, which is normalized upon consuming enough dietary levels of zinc.[193][194] This may be related to relatively high concentrations of zinc in some ear structures (cochlea and vestibule) where it exerts protective effects from stessors[195] possibly related to its role as a neuromodulator or as a component of Cu/Zn superoxide dismutase;[196] the latter of which is known to be protective of hearing.[197]

It has been hypothesized that zinc could be useful in the treatment of tinnitus,[198][196] although while some evidence suggests that persons with tinnitus are at higher rates of deficiency[199][200] other studies have failed to find an association.[201] At least one study has noted that 50mg zinc supplementation daily for two months is able to reduce the severity of tinnitus in 82% of patients given the supplement, with no significant reduction seen in placebo.[199]

The evidence is currently preliminary and only one trial has been conducted, but high dose zinc supplementation may potentially have a therapeutic role for tinnitus

In persons with idiopathic sudden sensorineural hearing loss (sudden hearing loss from unknown causes), the addition of zinc (gluconate) to oral corticosterone therapy was associated with a greater improvement in hearing than corticosterone alone.[202]

The addition of zinc supplementation to corticosteroids appears to accelerate the recovery of hearing after sudden idiopathic hearing loss


Zinc deficiency is known to cause testicular apoptosis (regulated cell death,[203] which tends to happen in many tissue types with zinc deficiency[204][205]) and increases protein oxidation in the testes while dysregulating the activity of 3β- and 17β-hydroxysteroid dehydrogenase enzymes[206] and other proteins[207] ultimately resulting in a degeneration of testicular structures (seminiferous tubules and leydig cells),[208] impaired testosterone secretion from the testes, and a reduction in fertility as sperm morphology and properties (such as motility) become progressively damaged alongside increasing testicular oxidation and apoptosis.[209][210][211]

A zinc deficiency is associated with wide-reaching impairment of testicular function including reduced testosterone synthesis and secretion, impaired fertility and sperm parameters, and increased rates of cell death

Orally supplemented zinc to research animals is able to reduce oxidative damage to the testicles (and the subsequent reduction in fertility markers) induced by cigarette smoke (20mg/kg zinc chloride).[154]

Supplemental zinc may reduce the damage done by oxidative stressors to the testes in rodents that are not inhernetly deficient in zinc

In infertile men, supplementation of zinc can increase sperm count only in men who also have low testosterone concentrations in their blood; this is associated with an increase in fertility, and not observed in men who are infertile with adequate testosterone concentrations.[156]

10Interactions with Cancer Metabolism

10.1Adjuvant Therapies

In persons given radiotherapy (for cancer treatment), 50mg zinc sulfate thrice daily with meals failed to reduce the development of oral mucositis or pharyngitis[212] which are common side-effects of radiotherapy to the head and neck region.[213] Other studies have noted a failure of 220mg zinc sulfate (50mg elemental zinc) twice daily in reducing severity or occurrence of mucositis.[214]

Some evidence does support a benefit for zinc supplementation in reducing the severity (but not incidence) or oral mucositis with 50mg elemental zinc (as sulfate) thrice daily alongside chemotherapy[215] or radiotherapy.[216]

The development of mucositis during radiotherapy and chemotherapy is unreliably treated with zinc supplementation

Alterations in taste (Dysgeusia) and smell (Dysosmia) commonly occur during chemotherapy[217] which are known to be associated with reductions in food intake (compounding cancer cachexia) and reduced quality of life.[218] Zinc is thought to be useful for this condition as it is a component of the salivary enzyme carbonic anhydrase VI which is a growth factor for sensory cells;[219] if the ageusia is caused form cell death then increasing cellular proliferation may be therapeutic, and in persons with carbonic anhydrase VI deficiencies zinc supplementation at 100mg for 4-6 months can improve dysgeusic symptoms secondary to proliferating carbonic anhydrase VI.[220]

It has been noted that improved dysgeusic symptoms only occur in persons who are deficient in carbonic anhydrase VI and respond to zinc supplementation (indicated by an increase in salivary zinc)[220] and other studies have noted that supplementation of zinc (50mg elemental zinc twice daily) to persons undergoing chemotherapy is not associated with a lessening of symptoms.[178]

Dysgeusia (alterations in taste) and smell associated with chemotherapy may be beneficially influenced in some persons, but this is not highly reliable

11Interactions with Aesthetics


Supplementation of zinc is sometimes recommended for the treatment of acne,[221] in part since serum levels of zinc are usually lower in persons with severe acne relative to controls[222][223][224] and thought to be related to the ability of zinc to reduce chemotaxis of immune cells to the skin[225][226] and possible its 5α-reductase inhibiting potential.

600mg zinc sulphate (138mg elemental zinc) over a period of six weeks in persons with acne appears to reduce symptoms by about a third, which was modestly but significantly more active than placebo.[227] This was later replicated with the same dose over 12 weeks with efficacy,[228] and an increase in serum Vitamin A was associated with zinc.

Later studies have confirmed efficacy with zinc gluconate (30mg elemental zinc) with a potency lesser than the reference drug minocycline as the amount of participants that met the primary end-point in the study (two thirds symptom reduction) was 31.2% and 63.4% for zinc and minocycline, respectively.[229] Efficacy with low dose zinc has been reported elsewhere.[230]

Zinc is known to be circulating at lower levels in persons with acne relative to those without, and it is thought to be therapeutic by reducing the migration of immune cells to the skin and possibly reducing the effects of androgens on the skin. Trials using zinc for acne control note that standard to high supplemental dosages have a modest protective effect

In response to viral warts from human papilloma virus (HPV), an open-label study using zinc sulfate at doses of 10mg/kg up to a maximum dose of 600mg/kg (132mg elemental zinc) over two months has found that half of the participants experienced complete resolution of their warts and remained free of warts and lesions when followed up at six months.[231] This has been noted elsewhere with recalcitrant viral warts in response to the same dose of oral supplementation[232] and topical zinc sulphate (5-10% of solution) also appears to be effective but to a greater degree (42.8-85.7% resolution).[233]

Warts that are not originated from a virus (common warts) have also noted benefit with topical application of zinc, but to a much lesser degree (5-11% with 5-10% zinc sulphate solution).[233]

2 months supplementation of very high dose zinc appears to be very effective in reducing viral warts, based on some preliminary evidence. The benefits may persist for a prolonged period of time after supplementation is ceased, and topical zinc also appears effective at high concentrations. Non-viral warts are not as potently suppressed

Rosacea is a chronic relapsing disease characterized by inflammatory eruption of the flush area of the face, usually manifesting as erythema (reddening) and a thickening of the skin resulting in phyma (overgrowth of sebaceous glands).[234]

100mg of zinc sulfate thrice daily in persons with rosacea has been noted to reduce symptoms of rosacea, although this study lacked a washout period between periods of the trial[235] and a later double blind to address this using 220mg zinc sulfate (50.8mg elemental zinc) twice daily for three months failed to find a significant effect.[236]

The human evidence in support of zinc as therapy for rosacea is currently small and mixed. While inefficacy of zinc in this role cannot yet be claimed, the evidence does not support usage of zinc for therapy of rosacea

50mg elemental zinc in psorasis patients thrice daily for six weeks is able to restore impaired chemotaxis of neutrophils.[225]

Topical zinc pyrithione has been reported (case studies) to improve symptoms of psoriasis[237] and subsequently a trial using this formulation (0.25% zinc pyrithione) to persons with psoriasis twice daily for three months reported improvements in induration, erythema, and scaling with a mean 70.5% reduction in symptoms as assessed by PASI.[238]

Limited evidence suggests that topical zinc pyrithione is highly effective for the treatment of psoriasis

12Sexuality and Pregnancy

12.1PMS and Menopause

A two-month placebo-controlled trial among high school students not on birth control with primary dysmennorrhea saw a reduction of pain as measured by a visual analog scale of 23% the first month and 61% the second month with zinc sulfate use.[239] The dose given was 220mg zinc sulfate three times a day for four days, starting the day before menstural bleeding commenced.[239]

13Interactions with Other Disease States


Zinc has a bimodal effect on the fibrillization and phosphorylation of a protein known as tau, similar in concept to β-amyloid proteins that form during Alzheimer's disease, as while high concentrations of zinc (250µM) promote this process[240][241] lower concentrations (100µM) are protective.[240] It can compete with copper for binding to β-amyloid proteins in an ultimately protective manner,[242] copper being more likely than zinc to promote oxidative damage from β-amyloid.[243]

In a mouse model for Alzheimer's, water with an additional 30ppm zinc given throughout the lifespan appeared to have protective effects relative to control in preventing the decline in memory.[69] This protective effect appeared to be associated with less protein (β-amyloid and tau) pathology as well as improvements in mitochondrial function and BDNF levels.[69]

13.2Celiac Disease

Celiac disease is a state characterized by small intestinal malabsorption of nutrients and increases in intestinal permeability that respond in particular to lectins from wheat (known as gluten), which is primarly treated with a gluten-free diet without an inherent need for medication.[244][245] In persons with celiac disease, this malabsporption may result in a relative zinc deficiency[246][247] although supplementation is not required if a gluten free diet (and thus less malabsorption) is adhered to.[248]

In somebody with celiac disease who consumes gluten (and thus experiences intestinal distress and malabsorption from their gluten intolerance), zinc absorption can be hindered and a deficiency can ensue. Avoiding gluten will avoid this complication and would then preclude the need to supplementation


Pruritus (itch) during hemodialysis is alleviated with 440mg zinc sulfate daily over the period of one month to a degree larger than placebo.[249]

14Nutrient-Nutrient Interactions

14.1Vitamin B6

Vitamin B6 (pyridoxine) is commonly supplemented alongside zinc and magnesium (as aspartate) in the formulation known as ZMA. This formulation is recommended in part due to both minerals being common deficiencies for athletes (and thus replenishment a priority), yet it is also claimed to be a Testosterone Booster.

It appears that the inhibitor effect of zinc on the 5α-reductase enzyme in vitro that can reach 98% at 15mM of zinc sulphate is potentiated by vitamin B6, as the addition of 0.025% B6 to the medium produced a similar levels of inhibition despite only using 1.5-3mM zinc sulphate.[160] Beyond the combination of those two, 500µM zinc sulphate paired with 0.025% B6 with an additional 100µM azelaic acid produced similarly potent inhibition[160] and this apparent synergism has been noted in skin cells as well[160] which is likely due to inhibition of 5α-reductase in particular.[163]

Complications with the above data is that zinc alone likely does not reach high enough concentrations in the human body to inhibit 5α-reductase, and at lower concentrations (500nM) it actually augments the activity of the enzyme[162] which may underlie increases in DHT seen in humans.[156] While high dose zinc supplementation paired with vitamin B6 can potentially be effective, this has not adequately been tested in humans.

While studies that investigate ZMA per se don't tend to measure DHT directly, there doesn't appear to be any increases in testosterone[250] which are supposed to be increased when the 5α-reductase enzyme is inhibited due to backlog (seen with finasteride[251]).

Zinc is inhernetly a potent 5α-reductase inhibitor (type I) and this potency is augmented by the addition of B6. While this leads to the assumption that the combination would cause an increase in testosterone at the expense of DHT, this doesn't appear to occur following oral supplementation of standard doses of either supplements. This may be due to such a large concentration being required for potent inhibition and this concentration just not occurring with oral supplementation of zinc, even after the requirements are lowered by B6


Alcohol is known to be teratogenic to the fetus, which may be related to zinc metabolism. Specifically, overconsumption of alcohol causes an increase in metallothionein[252] which then sequesters zinc[253] and its transportation to the fetus;[254] teratogenicity and cognitive impairment of the fetus can be attenuated with zinc consumption in mice[255][256][257][258] although this is not yet studied in humans.

Reductions in zinc concentrations in serum are associated with the adverse effects of alcohol on fetal development


Both zinc and iron are transported by the bivalent cation transporter DMT1[259] and Nramp2.[260] As transporters can get saturated to capacity with excessive levels of substrate, it is thought high levels of both minerals may impair absorption of one of them.

Supplementation of zinc in solution appears to inhibit the absorption of iron. with low doses of iron (500mcg) requiring 5.7-fold as much zinc to inhibit absorption while higher doses (10mg) only required a 1:1 ratio[261] which has been replicated.[262] Elsewhere, nonheme iron specifically, where a solution of zinc and iron caused a dose-dependent inhibition of 28-40% with increasing zinc ratios (5:1 to 20:1).[263]

Iron and zinc in solution appear to compete for absorption, and while this is not a concern with low levels of iron intake it does appear to be concernable when both minerals are above 10mg. This may be relevant to taking supplements containing them both in a fasted state

Studies using fortified milk (4:1 ratio with 300mcg/kg iron in infants[264] or simply 10mg/L iron with a 2:1 ratio in women[265]) have failed to replicate the inhibition of iron absorption.

Studies using iron and zinc both fortified into food products have failed to find a zinc-mediated inhibition of iron absorption. It is possible that this is related to a reduced rate of absorption (due to solid food particles in the intestines) and the reduced rate avoiding transporter saturation


Copper deficiency can be induced by disease states (Wilson disease and Menkes syndrome), excess losses (nephrotic syndrome) or inadequate dietary intake of copper; of interest to zinc is how zinc supplementation can induce a copper deficiency which has been reported in humans using up to 600mg elemental zinc daily[266] or excessive usage of zinc-based dental adhesives (a tube a day).[267][266][268]

The mechanism is through the proteins known as metallothioneins, which sequester some minerals (cadmium, zinc, and copper[269]) and control their oxidative effects. The protein seems to be inducable, being increased in content in response to the minerals that it sequesters[270] and it is thought that the higher levels of metallothionein can adequately sequester possible toxicity from zinc but overreact in sequestering copper, leading to its deficiency if copper is not also overconsumed.

Excessive zinc usage can increase levels of metallothioneins, which is due to this protein sequestering possible toxic effects of zinc excess. However, since it also sequesters copper it can lead to deficiencies in this latter mineral when the ratio of zinc:copper gets too high

This is sometimes therapeutic, as copper overload has been implicated in some disease states such as Alzheimer's[271][272] and liver cirrhosis.[186]

To a degree, this sequestering can be therapeutic. This has not been tested with the doses used to induce deficiences though, but with more modest 'superloading' protocols (100mg elemental zinc or so)

15Safety and Toxicology


A meta-analysis on the usage of zinc preparations for treating the common cold noted that zinc lozenges were associated with altered taste perception and nausea to a degree higher than placebo with a variable dose of 30-160mg elemental zinc.[125] This is seen in a few interventions with zinc for the treatment of pneumonia in children, where nausea and vomiting occurs at a greater frequency than placebo.[128]


  1. ^ a b Koehler K, et al. Serum testosterone and urinary excretion of steroid hormone metabolites after administration of a high-dose zinc supplement. Eur J Clin Nutr. (2009)
  2. ^ Weismann K, et al. Zinc gluconate lozenges for common cold. A double-blind clinical trial. Dan Med Bull. (1990)
  3. ^ Guéguen M, et al. Shellfish and residual chemical contaminants: hazards, monitoring, and health risk assessment along French coasts. Rev Environ Contam Toxicol. (2011)
  4. ^ Maret W, Sandstead HH. Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol. (2006)
  5. ^ Brown KH, Hambidge KM, Ranum P; Zinc Fortification Working Group. Zinc fortification of cereal flours: current recommendations and research needs. Food Nutr Bull. (2010)
  6. ^ Prasad AS. Zinc: an overview. Nutrition. (1995)
  7. ^ Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev. (1993)
  8. ^ Haase H, Rink L. Functional significance of zinc-related signaling pathways in immune cells. Annu Rev Nutr. (2009)
  9. ^ Anzellotti AI, Farrell NP. Zinc metalloproteins as medicinal targets. Chem Soc Rev. (2008)
  10. ^ Vallee BL, Auld DS. Zinc metallochemistry in biochemistry. EXS. (1995)
  11. ^ Abreu IA, Cabelli DE. Superoxide dismutases-a review of the metal-associated mechanistic variations. Biochim Biophys Acta. (2010)
  12. ^ Prasad AS. Zinc in human health: effect of zinc on immune cells. Mol Med. (2008)
  13. ^ Prasad AS. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp Gerontol. (2008)
  14. ^ Nutrient Reference Values for Australia and New Zealand: Zinc.
  15. ^ Recommended Dietary Allowances: 10th Edition.
  16. ^ Prasad AS. Clinical manifestations of zinc deficiency. Annu Rev Nutr. (1985)
  17. ^ Prasad AS. Zinc deficiency in human subjects. Prog Clin Biol Res. (1983)
  18. ^ a b Cope EC, Levenson CW. Role of zinc in the development and treatment of mood disorders. Curr Opin Clin Nutr Metab Care. (2010)
  19. ^ a b Takeda A, Tamano H. Insight into zinc signaling from dietary zinc deficiency. Brain Res Rev. (2009)
  20. ^ Quantifying Selected Major Risks to Health.
  21. ^ Hambidge M. Human zinc deficiency. J Nutr. (2000)
  22. ^ Lukaski HC. Magnesium, zinc, and chromium nutriture and physical activity. Am J Clin Nutr. (2000)
  23. ^ Campbell WW, Anderson RA. Effects of aerobic exercise and training on the trace minerals chromium, zinc and copper. Sports Med. (1987)
  24. ^ Galbo H, et al. Thyroid and testicular hormone responses to graded and prolonged exercise in man. Eur J Appl Physiol Occup Physiol. (1977)
  25. ^ Hackney AC, et al. Comparison of the hormonal responses to exhaustive incremental exercise in adolescent and young adult males. Arq Bras Endocrinol Metabol. (2011)
  26. ^ a b c d Canfield WK, Hambidge KM, Johnson LK. Zinc nutriture in type I diabetes mellitus: relationship to growth measures and metabolic control. J Pediatr Gastroenterol Nutr. (1984)
  27. ^ a b Kinlaw WB, et al. Abnormal zinc metabolism in type II diabetes mellitus. Am J Med. (1983)
  28. ^ a b McNair P, et al. Hyperzincuria in insulin treated diabetes mellitus--its relation to glucose homeostasis and insulin administration. Clin Chim Acta. (1981)
  29. ^ a b Zargar AH, et al. Copper, zinc and magnesium levels in type-1 diabetes mellitus. Saudi Med J. (2002)
  30. ^ a b c d Cellular zinc in patients with diabetes mellitus.
  31. ^ a b c d e Jansen J, et al. Disturbed zinc homeostasis in diabetic patients by in vitro and in vivo analysis of insulinomimetic activity of zinc. J Nutr Biochem. (2012)
  32. ^ a b Aguilar MV, et al. Plasma mineral content in type-2 diabetic patients and their association with the metabolic syndrome. Ann Nutr Metab. (2007)
  33. ^ a b Kiilerich S, et al. 65 zinc absorption in patients with insulin-dependent diabetes mellitus assessed by whole-body counting technique. Clin Chim Acta. (1990)
  34. ^ a b Williams NR, et al. Plasma, granulocyte and mononuclear cell copper and zinc in patients with diabetes mellitus. Analyst. (1995)
  35. ^ a b c Barrie SA, et al. Comparative absorption of zinc picolinate, zinc citrate and zinc gluconate in humans. Agents Actions. (1987)
  36. ^ Korolkiewicz RP, et al. Polaprezinc exerts a salutary effect on impaired healing of acute gastric lesions in diabetic rats. Dig Dis Sci. (2000)
  37. ^ Odenwald MA, Turner JR. Intestinal permeability defects: is it time to treat?. Clin Gastroenterol Hepatol. (2013)
  38. ^ a b c d e Mahmood A, et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. (2007)
  39. ^ a b Weigand E, Kirchgessner M. Homeostatic adjustments in zinc digestion to widely varying dietary zinc intake. Nutr Metab. (1978)
  40. ^ Effect of dietary zinc on 65-ZN absorption and turnover in rats.
  41. ^ Wada L, Turnlund JR, King JC. Zinc utilization in young men fed adequate and low zinc intakes. J Nutr. (1985)
  42. ^ Lee DY, et al. Homeostasis of zinc in marginal human zinc deficiency: role of absorption and endogenous excretion of zinc. J Lab Clin Med. (1993)
  43. ^ Taylor CM, et al. Homeostatic regulation of zinc absorption and endogenous losses in zinc-deprived men. Am J Clin Nutr. (1991)
  44. ^ Wong CP, Magnusson KR, Ho E. Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation. J Nutr Biochem. (2012)
  45. ^ Beiseigel JM, et al. Zinc absorption adapts to zinc supplementation in postmenopausal women. J Am Coll Nutr. (2009)
  46. ^ a b Wessells KR, et al. Plasma zinc concentration responds rapidly to the initiation and discontinuation of short-term zinc supplementation in healthy men. J Nutr. (2010)
  47. ^ a b Frederickson CJ, et al. Importance of zinc in the central nervous system: the zinc-containing neuron. J Nutr. (2000)
  48. ^ Barañano DE, Ferris CD, Snyder SH. Atypical neural messengers. Trends Neurosci. (2001)
  49. ^ Choi DW, Koh JY. Zinc and brain injury. Annu Rev Neurosci. (1998)
  50. ^ a b Frederickson CJ, et al. Cytoarchitectonic distribution of zinc in the hippocampus of man and the rat. Brain Res. (1983)
  51. ^ Harrison NL, Gibbons SJ. Zn2+: an endogenous modulator of ligand- and voltage-gated ion channels. Neuropharmacology. (1994)
  52. ^ Palm R, Hallmans G. Zinc concentrations in the cerebrospinal fluid of normal adults and patients with neurological diseases. J Neurol Neurosurg Psychiatry. (1982)
  53. ^ Wensink J, et al. The effect of dietary zinc deficiency on the mossy fiber zinc content of the rat hippocampus. A microbeam PIXE study. Particle Induced X-Ray Emission. Histochemistry. (1987)
  54. ^ a b Baltaci AK, Mogulkoc R. Pinealectomy and melatonin administration in rats: their effects on plasma leptin levels and relationship with zinc. Acta Biol Hung. (2007)
  55. ^ Spontaneous and evoked release of endogenous Zn2+ in the hippocampal mossy fiber zone of the rat in situ.
  56. ^ a b Sensi SL1, Yin HZ, Weiss JH. AMPA/kainate receptor-triggered Zn2+ entry into cortical neurons induces mitochondrial Zn2+ uptake and persistent mitochondrial dysfunction. Eur J Neurosci. (2000)
  57. ^ Dineley KE1, et al. Zinc causes loss of membrane potential and elevates reactive oxygen species in rat brain mitochondria. Mitochondrion. (2005)
  58. ^ a b Peters S, Koh J, Choi DW. Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons. Science. (1987)
  59. ^ Bancila V, et al. Zinc inhibits glutamate release via activation of pre-synaptic K channels and reduces ischaemic damage in rat hippocampus. J Neurochem. (2004)
  60. ^ Brambilla P1, et al. Corpus callosum signal intensity in patients with bipolar and unipolar disorder. J Neurol Neurosurg Psychiatry. (2004)
  61. ^ Wu JC1, et al. Magnetic resonance and positron emission tomography imaging of the corpus callosum: size, shape and metabolic rate in unipolar depression. J Affect Disord. (1993)
  62. ^ Reyes-Haro D1, et al. Uptake of serotonin by adult rat corpus callosum is partially reduced by common antidepressants. J Neurosci Res. (2003)
  63. ^ a b García-Colunga J1, et al. Zinc modulation of serotonin uptake in the adult rat corpus callosum. J Neurosci Res. (2005)
  64. ^ Klein AB1, et al. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol. (2011)
  65. ^ Leal G1, Comprido D, Duarte CB. BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology. (2014)
  66. ^ Adlam J1, Zaman R. The role of BDNF and memory in major depressive disorder. Psychiatr Danub. (2013)
  67. ^ a b Xu H1, et al. Lactational zinc deficiency-induced hippocampal neuronal apoptosis by a BDNF-independent TrkB signaling pathway. Hippocampus. (2011)
  68. ^ Travaglia A1, et al. Zinc(II) interactions with brain-derived neurotrophic factor N-terminal peptide fragments: inorganic features and biological perspectives. Inorg Chem. (2013)
  69. ^ a b c d Corona C1, et al. Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction. Cell Death Dis. (2010)
  70. ^ Hwang JJ1, et al. Activation of the Trk signaling pathway by extracellular zinc. Role of metalloproteinases. J Biol Chem. (2005)
  71. ^ a b c d e f Yang Y1, et al. High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling. PLoS One. (2013)
  72. ^ a b c Solati Z, et al. Zinc monotherapy increases serum brain-derived neurotrophic factor (BDNF) levels and decreases depressive symptoms in overweight or obese subjects: A double-blind, randomized, placebo-controlled trial. Nutr Neurosci. (2014)
  73. ^ a b Ranjbar E, et al. Effects of zinc supplementation on efficacy of antidepressant therapy, inflammatory cytokines, and brain-derived neurotrophic factor in patients with major depression. Nutr Neurosci. (2014)
  74. ^ a b Koh JY, et al. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science. (1996)
  75. ^ Choi DW. Zinc neurotoxicity may contribute to selective neuronal death following transient global cerebral ischemia. Cold Spring Harb Symp Quant Biol. (1996)
  76. ^ Lee JM, et al. Zinc translocation accelerates infarction after mild transient focal ischemia. Neuroscience. (2002)
  77. ^ Diener HC, et al. DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke. Stroke. (2008)
  78. ^ Pittenger C, Krystal JH, Coric V. Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder. NeuroRx. (2006)
  79. ^ Chakrabarty K, et al. Glutamatergic dysfunction in OCD. Neuropsychopharmacology. (2005)
  80. ^ Starck G, et al. A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity. J Neural Transm. (2008)
  81. ^ Coric V, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. (2005)
  82. ^ Sayyah M, et al. Evaluation of oral zinc sulfate effect on obsessive-compulsive disorder: a randomized placebo-controlled clinical trial. Nutrition. (2012)
  83. ^ Neurobiology of Zinc-Influenced Eating Behavior.
  84. ^ Tassabehji NM, et al. Zinc deficiency induces depression-like symptoms in adult rats. Physiol Behav. (2008)
  85. ^ a b c d Ohinata K, et al. Orally administered zinc increases food intake via vagal stimulation in rats. J Nutr. (2009)
  86. ^ Jing MY, Sun JY, Wang JF. The effect of peripheral administration of zinc on food intake in rats fed Zn-adequate or Zn-deficient diets. Biol Trace Elem Res. (2008)
  87. ^ Holst B, et al. GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology. (2007)
  88. ^ Inui A, et al. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. (2004)
  89. ^ Asakawa A, et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology. (2001)
  90. ^ Arnold LE, et al. Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine. J Child Adolesc Psychopharmacol. (2011)
  91. ^ Amani R, et al. Correlation between dietary zinc intakes and its serum levels with depression scales in young female students. Biol Trace Elem Res. (2010)
  92. ^ Siwek M, et al. Serum zinc level in depressed patients during zinc supplementation of imipramine treatment. J Affect Disord. (2010)
  93. ^ Maes M, et al. Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness. Biol Psychiatry. (1997)
  94. ^ Maes M, et al. Hypozincemia in depression. J Affect Disord. (1994)
  95. ^ a b Tamano H, et al. Behavior in the forced swim test and neurochemical changes in the hippocampus in young rats after 2-week zinc deprivation. Neurochem Int. (2009)
  96. ^ Watanabe M, et al. Susceptibility to stress in young rats after 2-week zinc deprivation. Neurochem Int. (2010)
  97. ^ a b c d Ilouz R, et al. Inhibition of glycogen synthase kinase-3beta by bivalent zinc ions: insight into the insulin-mimetic action of zinc. Biochem Biophys Res Commun. (2002)
  98. ^ Gould TD, et al. Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders. Curr Drug Targets. (2006)
  99. ^ Little KY, et al. Altered zinc metabolism in mood disorder patients. Biol Psychiatry. (1989)
  100. ^ Sawada T, Yokoi K. Effect of zinc supplementation on mood states in young women: a pilot study. Eur J Clin Nutr. (2010)
  101. ^ Stewart-Knox BJ, et al. Supplemented zinc does not alter mood in healthy older European adults--a randomised placebo-controlled trial: the Zenith study. Public Health Nutr. (2011)
  102. ^ Siwek M, et al. Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study. J Affect Disord. (2009)
  103. ^ a b c Tahmasebi Boroujeni S, et al. The effect of severe zinc deficiency and zinc supplement on spatial learning and memory. Biol Trace Elem Res. (2009)
  104. ^ a b c Flinn JM1, et al. Enhanced zinc consumption causes memory deficits and increased brain levels of zinc. Physiol Behav. (2005)
  105. ^ Mizuno M1, et al. Involvement of BDNF receptor TrkB in spatial memory formation. Learn Mem. (2003)
  106. ^ Piechal A1, et al. Maternal zinc supplementation improves spatial memory in rat pups. Biol Trace Elem Res. (2012)
  107. ^ Railey AM1, et al. Alterations in fear response and spatial memory in pre- and post-natal zinc supplemented rats: remediation by copper. Physiol Behav. (2010)
  108. ^ Aquilani R, et al. Normalization of zinc intake enhances neurological retrieval of patients suffering from ischemic strokes. Nutr Neurosci. (2009)
  109. ^ Hennig B, Toborek M, Mcclain CJ. Antiatherogenic properties of zinc: implications in endothelial cell metabolism. Nutrition. (1996)
  110. ^ Beattie JH, Kwun IS. Is zinc deficiency a risk factor for atherosclerosis. Br J Nutr. (2004)
  111. ^ Yang YJ, et al. Dietary zinc intake is inversely related to subclinical atherosclerosis measured by carotid intima-media thickness. Br J Nutr. (2010)
  112. ^ Bao B, et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr. (2010)
  113. ^ a b c Kelishadi R, et al. Effect of zinc supplementation on markers of insulin resistance, oxidative stress, and inflammation among prepubescent children with metabolic syndrome. Metab Syndr Relat Disord. (2010)
  114. ^ Jansen J, Karges W, Rink L. Zinc and diabetes--clinical links and molecular mechanisms. J Nutr Biochem. (2009)
  115. ^ Eldar-Finkelman H, Krebs EG. Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc Natl Acad Sci U S A. (1997)
  116. ^ Correlation between zinc status and immune function in the elderly.
  117. ^ Meftah S, et al. Ecto 5' nucleotidase (5'NT) as a sensitive indicator of human zinc deficiency. J Lab Clin Med. (1991)
  118. ^ a b c Blostein-Fujii A, et al. Short-term zinc supplementation in women with non-insulin-dependent diabetes mellitus: effects on plasma 5'-nucleotidase activities, insulin-like growth factor I concentrations, and lipoprotein oxidation rates in vitro. Am J Clin Nutr. (1997)
  119. ^ Hashemipour M, et al. Effect of zinc supplementation on insulin resistance and components of the metabolic syndrome in prepubertal obese children. Hormones (Athens). (2009)
  120. ^ Seet RC, et al. Oral zinc supplementation does not improve oxidative stress or vascular function in patients with type 2 diabetes with normal zinc levels. Atherosclerosis. (2011)
  121. ^ a b c d e f g Mantzoros CS, et al. Zinc may regulate serum leptin concentrations in humans. J Am Coll Nutr. (1998)
  122. ^ a b c Prasad AS, et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. (2007)
  123. ^ The Dynamic Link between the Integrity of the Immune System and Zinc Status.
  124. ^ Chandra RK. Excessive intake of zinc impairs immune responses. JAMA. (1984)
  125. ^ a b c Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. (2011)
  126. ^ Ganguly A, et al. A randomized controlled trial of oral zinc in acute pneumonia in children aged between 2 months to 5 years. Indian J Pediatr. (2011)
  127. ^ Wadhwa N, et al. Efficacy of zinc given as an adjunct in the treatment of severe and very severe pneumonia in hospitalized children 2-24 mo of age: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. (2013)
  128. ^ a b Valentiner-Branth P, et al. A randomized controlled trial of the effect of zinc as adjuvant therapy in children 2-35 mo of age with severe or nonsevere pneumonia in Bhaktapur, Nepal. Am J Clin Nutr. (2010)
  129. ^ Shah GS, et al. Role of zinc in severe pneumonia: a randomized double bind placebo controlled study. Ital J Pediatr. (2012)
  130. ^ a b c Srinivasan MG, et al. Zinc adjunct therapy reduces case fatality in severe childhood pneumonia: a randomized double blind placebo-controlled trial. BMC Med. (2012)
  131. ^ Basnet S, et al. A randomized controlled trial of zinc as adjuvant therapy for severe pneumonia in young children. Pediatrics. (2012)
  132. ^ Valavi E, et al. The efficacy of zinc supplementation on outcome of children with severe pneumonia. A randomized double-blind placebo-controlled clinical trial. Indian J Pediatr. (2011)
  133. ^ Chandyo RK, et al. Two weeks of zinc administration to Nepalese children with pneumonia does not reduce the incidence of pneumonia or diarrhea during the next six months. J Nutr. (2010)
  134. ^ Baum MK, et al. HIV-1 infection in women is associated with severe nutritional deficiencies. J Acquir Immune Defic Syndr Hum Retrovirol. (1997)
  135. ^ Beach RS, et al. Specific nutrient abnormalities in asymptomatic HIV-1 infection. AIDS. (1992)
  136. ^ Jones CY, et al. Micronutrient levels and HIV disease status in HIV-infected patients on highly active antiretroviral therapy in the Nutrition for Healthy Living cohort. J Acquir Immune Defic Syndr. (2006)
  137. ^ Graham NM, et al. Relationship of serum copper and zinc levels to HIV-1 seropositivity and progression to AIDS. J Acquir Immune Defic Syndr. (1991)
  138. ^ Falutz J, Tsoukas C, Gold P. Zinc as a cofactor in human immunodeficiency virus-induced immunosuppression. JAMA. (1988)
  139. ^ Baum MK, et al. Zinc status in human immunodeficiency virus type 1 infection and illicit drug use. Clin Infect Dis. (2003)
  140. ^ Tang AM, et al. Dietary micronutrient intake and risk of progression to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus type 1 (HIV-1)-infected homosexual men. Am J Epidemiol. (1993)
  141. ^ Baum MK, et al. Randomized, controlled clinical trial of zinc supplementation to prevent immunological failure in HIV-infected adults. Clin Infect Dis. (2010)
  142. ^ Mocchegiani E, et al. Benefit of oral zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic infections in AIDS. Int J Immunopharmacol. (1995)
  143. ^ Han YS, et al. Papain-like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization, and inhibition. Biochemistry. (2005)
  144. ^ Hsu JT, et al. Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV. FEBS Lett. (2004)
  145. ^ Kara E, et al. Effect of zinc supplementation on antioxidant activity in young wrestlers. Biol Trace Elem Res. (2010)
  146. ^ Chang CS, et al. Correlation between serum testosterone level and concentrations of copper and zinc in hair tissue. Biol Trace Elem Res. (2011)
  147. ^ Prasad AS, et al. Zinc status and serum testosterone levels of healthy adults. Nutrition. (1996)
  148. ^ Zeng Q, et al. Associations of urinary metal concentrations and circulating testosterone in Chinese men. Reprod Toxicol. (2013)
  149. ^ Lei KY, Abbasi A, Prasad AS. Function of pituitary-gonadal axis in zinc-deficient rats. Am J Physiol. (1976)
  150. ^ a b Om AS, Chung KW. Dietary zinc deficiency alters 5 alpha-reduction and aromatization of testosterone and androgen and estrogen receptors in rat liver. J Nutr. (1996)
  151. ^ Chung KW, et al. Androgen receptors in ventral prostate glands of zinc deficient rats. Life Sci. (1986)
  152. ^ Habib FK. Zinc and the steroid endocrinology of the human prostate. J Steroid Biochem. (1978)
  153. ^ Kaya O, et al. Zinc supplementation in rats subjected to acute swimming exercise: Its effect on testosterone levels and relation with lactate. Neuro Endocrinol Lett. (2006)
  154. ^ a b Sankako MK, et al. Possible mechanism by which zinc protects the testicular function of rats exposed to cigarette smoke. Pharmacol Rep. (2012)
  155. ^ Jalali GR, et al. Impact of oral zinc therapy on the level of sex hormones in male patients on hemodialysis. Ren Fail. (2010)
  156. ^ a b c d Netter A, Hartoma R, Nahoul K. Effect of zinc administration on plasma testosterone, dihydrotestosterone, and sperm count. Arch Androl. (1981)
  157. ^ a b Shafiei Neek L, Gaeini AA, Choobineh S. Effect of zinc and selenium supplementation on serum testosterone and plasma lactate in cyclist after an exhaustive exercise bout. Biol Trace Elem Res. (2011)
  158. ^ a b Kilic M, et al. The effect of exhaustion exercise on thyroid hormones and testosterone levels of elite athletes receiving oral zinc. Neuro Endocrinol Lett. (2006)
  159. ^ Kilic M. Effect of fatiguing bicycle exercise on thyroid hormone and testosterone levels in sedentary males supplemented with oral zinc. Neuro Endocrinol Lett. (2007)
  160. ^ a b c d e Stamatiadis D, Bulteau-Portois MC, Mowszowicz I. Inhibition of 5 alpha-reductase activity in human skin by zinc and azelaic acid. Br J Dermatol. (1988)
  161. ^ Fahim MS, et al. Zinc arginine, a 5 alpha-reductase inhibitor, reduces rat ventral prostate weight and DNA without affecting testicular function. Andrologia. (1993)
  162. ^ a b Leake A, Chisholm GD, Habib FK. The effect of zinc on the 5 alpha-reduction of testosterone by the hyperplastic human prostate gland. J Steroid Biochem. (1984)
  163. ^ a b Sugimoto Y, et al. Cations inhibit specifically type I 5 alpha-reductase found in human skin. J Invest Dermatol. (1995)
  164. ^ a b Cesur Y, Yordaman N, Doğan M. Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels in children with zinc deficiency and the effect of zinc supplementation on these parameters. J Pediatr Endocrinol Metab. (2009)
  165. ^ Rodondi A, et al. Zinc increases the effects of essential amino acids-whey protein supplements in frail elderly. J Nutr Health Aging. (2009)
  166. ^ Konukoglu D, et al. Relationship between plasma leptin and zinc levels and the effect of insulin and oxidative stress on leptin levels in obese diabetic patients. J Nutr Biochem. (2004)
  167. ^ Ott ES, Shay NF. Zinc deficiency reduces leptin gene expression and leptin secretion in rat adipocytes. Exp Biol Med (Maywood). (2001)
  168. ^ Kwun IS, et al. Marginal zinc deficiency in rats decreases leptin expression independently of food intake and corticotrophin-releasing hormone in relation to food intake. Br J Nutr. (2007)
  169. ^ Saladin R, et al. Transient increase in obese gene expression after food intake or insulin administration. Nature. (1995)
  170. ^ Grunfeld C, et al. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest. (1996)
  171. ^ Beck FW, et al. Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. Am J Physiol. (1997)
  172. ^ Human Zinc Deficiency.
  173. ^ Gustin concentration changes relative to salivary zinc and taste in humans.
  174. ^ Heyneman CA. Zinc deficiency and taste disorders. Ann Pharmacother. (1996)
  175. ^ Tupe RP, Chiplonkar SA. Zinc supplementation improved cognitive performance and taste acuity in Indian adolescent girls. J Am Coll Nutr. (2009)
  176. ^ Mahmoodi MR, Kimiagar SM. Prevalence of zinc deficiency in junior high school students of Tehran City. Biol Trace Elem Res. (2001)
  177. ^ Hettiarachchi M, et al. Prevalence and severity of micronutrient deficiency: a cross-sectional study among adolescents in Sri Lanka. Asia Pac J Clin Nutr. (2006)
  178. ^ a b Lyckholm L, et al. A randomized, placebo controlled trial of oral zinc for chemotherapy-related taste and smell disorders. J Pain Palliat Care Pharmacother. (2012)
  179. ^ Uçkardeş Y, et al. The effect of systemic zinc supplementation on oral health in low socioeconomic level children. Turk J Pediatr. (2009)
  180. ^ Kirchhoff P, et al. Zinc salts provide a novel, prolonged and rapid inhibition of gastric acid secretion. Am J Gastroenterol. (2011)
  181. ^ Sturniolo GC, et al. Inhibition of gastric acid secretion reduces zinc absorption in man. J Am Coll Nutr. (1991)
  182. ^ Loguercio C, et al. Trace elements and chronic liver diseases. J Trace Elem Med Biol. (1997)
  183. ^ a b Nakayama A, et al. A new diagnostic method for chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma based on serum metallothionein, copper, and zinc levels. Biol Pharm Bull. (2002)
  184. ^ Lin CC, et al. Selenium, iron, copper, and zinc levels and copper-to-zinc ratios in serum of patients at different stages of viral hepatic diseases. Biol Trace Elem Res. (2006)
  185. ^ Nutritional Status and Blood Trace Elements in Cirrhotic Patients.
  186. ^ a b Somi MH, et al. Effects of low dose zinc supplementation on biochemical markers in non-alcoholic cirrhosis: a randomized clinical trial. Arch Iran Med. (2012)
  187. ^ Sturniolo GC, et al. Zinc supplementation tightens "leaky gut" in Crohn's disease. Inflamm Bowel Dis. (2001)
  188. ^ Zinc Supplementation Inhibits Hepatic Apoptosis in Mice Subjected to a Long-Term Ethanol Exposure.
  189. ^ Preservation of Intestinal Structural Integrity by Zinc Is Independent of Metallothionein in Alcohol-Intoxicated Mice.
  190. ^ Zhou Z, et al. Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress. Am J Pathol. (2005)
  191. ^ Zinc Deficiency Mediates Alcohol-Induced Alveolar Epithelial and Macrophage Dysfunction in Rats.
  192. ^ Kang YJ, Zhou Z. Zinc prevention and treatment of alcoholic liver disease. Mol Aspects Med. (2005)
  193. ^ Kang WS, et al. Effects of a zinc-deficient diet on hearing in CBA mice. Neuroreport. (2012)
  194. ^ Hoeve LJ, Wensink J, Mertens zur Borg IR. Hearing loss related to zinc deficiency in rats. Eur Arch Otorhinolaryngol. (1990)
  195. ^ Franco-Vidal V, et al. Zinc protection against pneumolysin toxicity on rat cochlear hair cells. Audiol Neurootol. (2008)
  196. ^ a b Coelho CB, Tyler R, Hansen M. Zinc as a possible treatment for tinnitus. Prog Brain Res. (2007)
  197. ^ Sha SH, et al. Overexpression of copper/zinc-superoxide dismutase protects from kanamycin-induced hearing loss. Audiol Neurootol. (2001)
  198. ^ Shambaugh GE Jr. Zinc for tinnitus, imbalance, and hearing loss in the elderly. Am J Otol. (1986)
  199. ^ a b Arda HN, et al. The role of zinc in the treatment of tinnitus. Otol Neurotol. (2003)
  200. ^ Ochi K, et al. Zinc deficiency and tinnitus. Auris Nasus Larynx. (2003)
  201. ^ Yetiser S, et al. The role of zinc in management of tinnitus. Auris Nasus Larynx. (2002)
  202. ^ Yang CH, et al. Zinc in the treatment of idiopathic sudden sensorineural hearing loss. Laryngoscope. (2011)
  203. ^ Kumari D, Nair N, Bedwal RS. Testicular apoptosis after dietary zinc deficiency: ultrastructural and TUNEL studies. Syst Biol Reprod Med. (2011)
  204. ^ Clegg MS, et al. Zinc deficiency-induced cell death. IUBMB Life. (2005)
  205. ^ Nodera M, Yanagisawa H, Wada O. Increased apoptosis in a variety of tissues of zinc-deficient rats. Life Sci. (2001)
  206. ^ Kumari D, Nair N, Bedwal RS. Protein carbonyl, 3β-, and 17β-hydroxysteroid dehydrogenases in testes and serum FSH, LH, and testosterone levels in zinc deficient Wistar rats. Biofactors. (2012)
  207. ^ Bahuguna A, Bedwal RS. Testicular protein profile (SDS-PAGE) study of zinc deficient Wistar albino rat. Indian J Exp Biol. (2008)
  208. ^ Kumari D, Nair N, Bedwal RS. Effect of dietary zinc deficiency on testes of Wistar rats: Morphometric and cell quantification studies. J Trace Elem Med Biol. (2011)
  209. ^ Merrells KJ, et al. Relationship between abnormal sperm morphology induced by dietary zinc deficiency and lipid composition in testes of growing rats. Br J Nutr. (2009)
  210. ^ Croxford TP, McCormick NH, Kelleher SL. Moderate zinc deficiency reduces testicular Zip6 and Zip10 abundance and impairs spermatogenesis in mice. J Nutr. (2011)
  211. ^ Yamaguchi S, et al. Zinc is an essential trace element for spermatogenesis. Proc Natl Acad Sci U S A. (2009)
  212. ^ Sangthawan D, Phungrassami T, Sinkitjarurnchai W. A randomized double-blind, placebo-controlled trial of zinc sulfate supplementation for alleviation of radiation-induced oral mucositis and pharyngitis in head and neck cancer patients. J Med Assoc Thai. (2013)
  213. ^ Saadeh CE. Chemotherapy- and radiotherapy-induced oral mucositis: review of preventive strategies and treatment. Pharmacotherapy. (2005)
  214. ^ Mansouri A, et al. The effect of zinc sulfate in the prevention of high-dose chemotherapy-induced mucositis: a double-blind, randomized, placebo-controlled study. Hematol Oncol. (2012)
  215. ^ Arbabi-kalati F, et al. Evaluation of the efficacy of zinc sulfate in the prevention of chemotherapy-induced mucositis: a double-blind randomized clinical trial. Arch Iran Med. (2012)
  216. ^ Ertekin MV, et al. Zinc sulfate in the prevention of radiation-induced oropharyngeal mucositis: a prospective, placebo-controlled, randomized study. Int J Radiat Oncol Biol Phys. (2004)
  217. ^ Halyard MY. Taste and smell alterations in cancer patients--real problems with few solutions. J Support Oncol. (2009)
  218. ^ Hong JH, et al. Taste and odor abnormalities in cancer patients. J Support Oncol. (2009)
  219. ^ Henkin RI, Martin BM, Agarwal RP. Decreased parotid saliva gustin/carbonic anhydrase VI secretion: an enzyme disorder manifested by gustatory and olfactory dysfunction. Am J Med Sci. (1999)
  220. ^ a b Henkin RI, Martin BM, Agarwal RP. Efficacy of exogenous oral zinc in treatment of patients with carbonic anhydrase VI deficiency. Am J Med Sci. (1999)
  221. ^ Dreno B, et al. Acne: evolution of the clinical practice and therapeutic management of acne between 1996 and 2000. Eur J Dermatol. (2003)
  222. ^ Ozuguz P, et al. Evaluation of serum vitamins A and E and zinc levels according to the severity of acne vulgaris. Cutan Ocul Toxicol. (2013)
  223. ^ Michaëlsson G, Vahlquist A, Juhlin L. Serum zinc and retinol-binding protein in acne. Br J Dermatol. (1977)
  224. ^ Nasiri S, et al. Serum zinc levels in Iranian patients with acne. Clin Exp Dermatol. (2009)
  225. ^ a b Leibovici V, et al. Effect of zinc therapy on neutrophil chemotaxis in psoriasis. Isr J Med Sci. (1990)
  226. ^ Dreno B, et al. Zinc salts effects on granulocyte zinc concentration and chemotaxis in acne patients. Acta Derm Venereol. (1992)
  227. ^ Göransson K, Lidén S, Odsell L. Oral zinc in acne vulgaris: a clinical and methodological study. Acta Derm Venereol. (1978)
  228. ^ Verma KC, Saini AS, Dhamija SK. Oral zinc sulphate therapy in acne vulgaris: a double-blind trial. Acta Derm Venereol. (1980)
  229. ^ Dreno B, et al. Multicenter randomized comparative double-blind controlled clinical trial of the safety and efficacy of zinc gluconate versus minocycline hydrochloride in the treatment of inflammatory acne vulgaris. Dermatology. (2001)
  230. ^ Dreno B, et al. Low doses of zinc gluconate for inflammatory acne. Acta Derm Venereol. (1989)
  231. ^ Mun JH, et al. Oral zinc sulfate treatment for viral warts: an open-label study. J Dermatol. (2011)
  232. ^ Al-Gurairi FT, Al-Waiz M, Sharquie KE. Oral zinc sulphate in the treatment of recalcitrant viral warts: randomized placebo-controlled clinical trial. Br J Dermatol. (2002)
  233. ^ a b Sharquie KE, Khorsheed AA, Al-Nuaimy AA. Topical zinc sulphate solution for treatment of viral warts. Saudi Med J. (2007)
  234. ^ Chapter 43. Rosacea, Perioral Dermatitis and Similar Dermatoses, Flushing and Flushing Syndromes.
  235. ^ Sharquie KE, Najim RA, Al-Salman HN. Oral zinc sulfate in the treatment of rosacea: a double-blind, placebo-controlled study. Int J Dermatol. (2006)
  236. ^ Bamford JT, et al. Randomized, double-blind trial of 220 mg zinc sulfate twice daily in the treatment of rosacea. Int J Dermatol. (2012)
  237. ^ Crutchfield CE 3rd, Lewis EJ, Zelickson BD. The highly effective use of topical zinc pyrithione in the treatment of psoriasis: a case report. Dermatol Online J. (1997)
  238. ^ Sadeghian G, Ziaei H, Nilforoushzadeh MA. Treatment of localized psoriasis with a topical formulation of zinc pyrithione. Acta Dermatovenerol Alp Panonica Adriat. (2011)
  239. ^ a b Kashefi F1, et al. Comparison of the effect of ginger and zinc sulfate on primary dysmenorrhea: a placebo-controlled randomized trial. Pain Manag Nurs. (2014)
  240. ^ a b Boom A1, et al. Bimodal modulation of tau protein phosphorylation and conformation by extracellular Zn2+ in human-tau transfected cells. Biochim Biophys Acta. (2009)
  241. ^ Mo ZY1, et al. Low micromolar zinc accelerates the fibrillization of human tau via bridging of Cys-291 and Cys-322. J Biol Chem. (2009)
  242. ^ Cuajungco MP1, Fagét KY. Zinc takes the center stage: its paradoxical role in Alzheimer's disease. Brain Res Brain Res Rev. (2003)
  243. ^ Bush AI1, Tanzi RE. Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics. (2008)
  244. ^ Harris LA, et al. Celiac disease: clinical, endoscopic, and histopathologic review. Gastrointest Endosc. (2012)
  245. ^ Rostom A, et al. The diagnostic accuracy of serologic tests for celiac disease: a systematic review. Gastroenterology. (2005)
  246. ^ Singhal N, et al. Serum zinc levels in celiac disease. Indian Pediatr. (2008)
  247. ^ Solomons NW, Rosenberg IH, Sandstead HH. Zinc nutrition in celiac sprue. Am J Clin Nutr. (1976)
  248. ^ Rawal P, et al. Zinc supplementation to patients with celiac disease--is it required. J Trop Pediatr. (2010)
  249. ^ Najafabadi MM, et al. Zinc sulfate for relief of pruritus in patients on maintenance hemodialysis. Ther Apher Dial. (2012)
  250. ^ Wilborn CD, et al. Effects of Zinc Magnesium Aspartate (ZMA) Supplementation on Training Adaptations and Markers of Anabolism and Catabolism. J Int Soc Sports Nutr. (2004)
  251. ^ Roehrborn CG, et al. Effects of finasteride on serum testosterone and body mass index in men with benign prostatic hyperplasia. Urology. (2003)
  252. ^ Uddin RK, Singh SM. Ethanol-responsive genes: identification of transcription factors and their role in metabolomics. Pharmacogenomics J. (2007)
  253. ^ Carey LC, et al. Maternal ethanol exposure is associated with decreased plasma zinc and increased fetal abnormalities in normal but not metallothionein-null mice. Alcohol Clin Exp Res. (2000)
  254. ^ Carey LC, et al. Ethanol decreases zinc transfer to the fetus in normal but not metallothionein-null mice. Alcohol Clin Exp Res. (2000)
  255. ^ Carey LC, et al. Zinc supplementation at the time of ethanol exposure ameliorates teratogenicity in mice. Alcohol Clin Exp Res. (2003)
  256. ^ Summers BL, Rofe AM, Coyle P. Dietary zinc supplementation throughout pregnancy protects against fetal dysmorphology and improves postnatal survival after prenatal ethanol exposure in mice. Alcohol Clin Exp Res. (2009)
  257. ^ Summers BL, et al. Dietary zinc supplementation during pregnancy prevents spatial and object recognition memory impairments caused by early prenatal ethanol exposure. Behav Brain Res. (2008)
  258. ^ Summers BL, Rofe AM, Coyle P. Prenatal zinc treatment at the time of acute ethanol exposure limits spatial memory impairments in mouse offspring. Pediatr Res. (2006)
  259. ^ Gunshin H, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. (1997)
  260. ^ Tandy S, et al. Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. J Biol Chem. (2000)
  261. ^ Olivares M, et al. Acute inhibition of iron bioavailability by zinc: studies in humans. Biometals. (2012)
  262. ^ Olivares M, Pizarro F, Ruz M. New insights about iron bioavailability inhibition by zinc. Nutrition. (2007)
  263. ^ Olivares M, Pizarro F, Ruz M. Zinc inhibits nonheme iron bioavailability in humans. Biol Trace Elem Res. (2007)
  264. ^ Friel JK, et al. Elevated intakes of zinc in infant formulas don not interfere with iron absorption in premature infants. J Pediatr Gastroenterol Nutr. (1998)
  265. ^ Olivares M, et al. Effect of increasing concentrations of zinc on the absorption of iron from iron-fortified milk. Biol Trace Elem Res. (2012)
  266. ^ a b Willis MS, et al. Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol. (2005)
  267. ^ Afrin LB. Fatal copper deficiency from excessive use of zinc-based denture adhesive. Am J Med Sci. (2010)
  268. ^ Nations SP, et al. Denture cream: an unusual source of excess zinc, leading to hypocupremia and neurologic disease. Neurology. (2008)
  269. ^ Cousins RJ. Metallothionein--aspects related to copper and zinc metabolism. J Inherit Metab Dis. (1983)
  270. ^ Induction of Kidney Metallothionein and Metallothionein Messenger RNA by Zinc and Cadmium.
  271. ^ Brewer GJ. Copper excess, zinc deficiency, and cognition loss in Alzheimer's disease. Biofactors. (2012)
  272. ^ Brewer GJ. Copper toxicity in Alzheimer's disease: cognitive loss from ingestion of inorganic copper. J Trace Elem Med Biol. (2012)
  273. Rashidi AA, et al. Effects of zinc supplementation on serum zinc and C-reactive protein concentrations in hemodialysis patients. J Ren Nutr. (2009)
  274. Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM Open. (2017)
  275. Jafari F, Amani R, Tarrahi MJ. Effect of Zinc Supplementation on Physical and Psychological Symptoms, Biomarkers of Inflammation, Oxidative Stress, and Brain-Derived Neurotrophic Factor in Young Women with Premenstrual Syndrome: a Randomized, Double-Blind, Placebo-Controlled Trial. Biol Trace Elem Res. (2019)
  276. Siahbazi S, et al. Effect of zinc sulfate supplementation on premenstrual syndrome and health-related quality of life: Clinical randomized controlled trial. J Obstet Gynaecol Res. (2017)
  277. Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother. (1984)
  278. Smith DS, et al. Failure of zinc gluconate in treatment of acute upper respiratory tract infections. Antimicrob Agents Chemother. (1989)
  279. Godfrey JC, et al. Zinc gluconate and the common cold: a controlled clinical study. J Int Med Res. (1992)
  280. Mossad SB, et al. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med. (1996)
  281. Prasad AS, et al. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. (2000)
  282. Prasad AS, et al. Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate. J Infect Dis. (2008)
  283. Turner RB, Cetnarowski WE. Effect of treatment with zinc gluconate or zinc acetate on experimental and natural colds. Clin Infect Dis. (2000)
  284. Hemilä H, et al. Zinc acetate lozenges for the treatment of the common cold: a randomised controlled trial. BMJ Open. (2020)
  285. Al-Nakib W, et al. Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges. J Antimicrob Chemother. (1987)
  286. Farr BM, et al. Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds. Antimicrob Agents Chemother. (1987)
  287. Ebben M, Lequerica A, Spielman A. Effects of pyridoxine on dreaming: a preliminary study. Percept Mot Skills. (2002)
  288. De Souza MC, et al. A synergistic effect of a daily supplement for 1 month of 200 mg magnesium plus 50 mg vitamin B6 for the relief of anxiety-related premenstrual symptoms: a randomized, double-blind, crossover study. J Womens Health Gend Based Med. (2000)
  289. Maggio M, et al. The Interplay between Magnesium and Testosterone in Modulating Physical Function in Men. Int J Endocrinol. (2014)
  290. Maggio M, et al. Magnesium and anabolic hormones in older men. Int J Androl. (2011)
  291. Rodgers S, et al. Serum testosterone levels and symptom-based depression subtypes in men. Front Psychiatry. (2015)
  292. Johnson JM, Nachtigall LB, Stern TA. The effect of testosterone levels on mood in men: a review. Psychosomatics. (2013)
  293. Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. (2009)
  294. Zarrouf FA, et al. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract. (2009)
  295. Davis SR, Wahlin-Jacobsen S. Testosterone in women--the clinical significance. Lancet Diabetes Endocrinol. (2015)
  296. Martínez-Cengotitabengoa M, González-Pinto A. Nutritional supplements in depressive disorders. Actas Esp Psiquiatr. (2017)
  297. Cortese BM, Phan KL. The role of glutamate in anxiety and related disorders. CNS Spectr. (2005)
  298. Bergink V, van Megen HJ, Westenberg HG. Glutamate and anxiety. Eur Neuropsychopharmacol. (2004)
  299. Tarleton EK, Littenberg B. Magnesium intake and depression in adults. J Am Board Fam Med. (2015)
  300. Derom ML, et al. Magnesium and depression: a systematic review. Nutr Neurosci. (2013)
  301. Boyle NB, Lawton C, Dye L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients. (2017)
  302. Fard FE, et al. Effects of zinc and magnesium supplements on postpartum depression and anxiety: A randomized controlled clinical trial. Women Health. (2017)
  303. Phelan D, et al. Magnesium and mood disorders: systematic review and meta-analysis. BJPsych Open. (2018)
  304. Nielsen FH, Lukaski HC. Update on the relationship between magnesium and exercise. Magnes Res. (2006)
  305. Costello RB, Moser-Veillon PB. A review of magnesium intake in the elderly. A cause for concern?. Magnes Res. (1992)
  306. Tang YM, et al. Relationships between micronutrient losses in sweat and blood pressure among heat-exposed steelworkers. Ind Health. (2016)
  307. Institute of Medicine (US) Committee on Military Nutrition Research; Marriott BM, editor. Washington (DC). Nutritional Needs in Hot Environments, “Influence of Exercise and Heat on Magnesium Metabolism”. National Academies Press (US). (1993)
  308. Consolazio CF, et al. Excretion of sodium, potassium, magnesium and iron in human sweat and the relation of each to balance and requirements. J Nutr. (1963)
  309. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride, page 242.
  310. Yoshimura Y, et al. Pharmacokinetic Studies of Orally Administered Magnesium Oxide in Rats. Yakugaku Zasshi. (2017)
  311. Firoz M, Graber M. Bioavailability of US commercial magnesium preparations. Magnes Res. (2001)
  312. Li Z, et al. Association of total zinc, iron, copper and selenium intakes with depression in the US adults. J Affect Disord. (2018)
  313. Roy A, et al. Higher zinc intake buffers the impact of stress on depressive symptoms in pregnancy. Nutr Res. (2010)
  314. Ranjbar E, et al. Effects of zinc supplementation in patients with major depression: a randomized clinical trial. Iran J Psychiatry. (2013)
  315. Swardfager W, et al. Potential roles of zinc in the pathophysiology and treatment of major depressive disorder. Neurosci Biobehav Rev. (2013)
  316. Nowak G, et al. Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Pol J Pharmacol. (2003)
  317. Institute of Medicine (US) Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc.
  318. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc, page 446.
  319. Meunier N, et al. Importance of zinc in the elderly: the ZENITH study. Eur J Clin Nutr. (2005)
  320. Blumberg J. Nutritional needs of seniors. J Am Coll Nutr. (1997)
  321. Tipton K, et al. Zinc loss in sweat of athletes exercising in hot and neutral temperatures. Int J Sport Nutr. (1993)
  322. Parker GB, Brotchie H, Graham RK. Vitamin D and depression. J Affect Disord. (2017)
  323. Allan GM, et al. Vitamin D: A Narrative Review Examining the Evidence for Ten Beliefs. J Gen Intern Med. (2016)
  324. Nair R, Maseeh A. Vitamin D: The "sunshine" vitamin. J Pharmacol Pharmacother. (2012)
  325. Holick MF. Vitamin D deficiency. N Engl J Med. (2007)
  326. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. (2011)
  327. Melrose S. Seasonal Affective Disorder: An Overview of Assessment and Treatment Approaches. Depress Res Treat. (2015)
  328. Kerr DC, et al. Associations between vitamin D levels and depressive symptoms in healthy young adult women. Psychiatry Res. (2015)
  329. O'Hare C, et al. Seasonal and meteorological associations with depressive symptoms in older adults: A geo-epidemiological study. J Affect Disord. (2016)
  330. Golden RN, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry. (2005)
  331. Lam RW, et al. The Can-SAD study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am J Psychiatry. (2006)
  332. Vellekkatt F, Menon V. Efficacy of vitamin D supplementation in major depression: A meta-analysis of randomized controlled trials. J Postgrad Med. (2018)
  333. Spedding S. Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients. (2014)
  334. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, et al. Dietary Reference Intakes for Calcium and Vitamin D.
  335. Cashman KD, et al. Improved Dietary Guidelines for Vitamin D: Application of Individual Participant Data (IPD)-Level Meta-Regression Analyses. Nutrients. (2017)
  336. Heaney R, et al. Letter to Veugelers, P.J. and Ekwaru, J.P., A statistical error in the estimation of the recommended dietary allowance for vitamin D. Nutrients 2014, 6, 4472-4475; doi:10.3390/nu6104472. Nutrients. (2015)
  337. Veugelers PJ, Ekwaru JP. A statistical error in the estimation of the recommended dietary allowance for vitamin D. Nutrients. (2014)
  338. Grosso G, et al. Dietary n-3 PUFA, fish consumption and depression: A systematic review and meta-analysis of observational studies. J Affect Disord. (2016)
  339. Mocking RJ, et al. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl Psychiatry. (2016)
  340. Burhani MD, Rasenick MM. Fish oil and depression: The skinny on fats. J Integr Neurosci. (2017)
  341. Bastiaansen JA, et al. The efficacy of fish oil supplements in the treatment of depression: food for thought. Transl Psychiatry. (2016)
  342. Lane K, et al. Bioavailability and potential uses of vegetarian sources of omega-3 fatty acids: a review of the literature. Crit Rev Food Sci Nutr. (2014)
  343. Hussein N, et al. Long-chain conversion of 13Clinoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men. J Lipid Res. (2005)
  344. Pawlosky RJ, et al. Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans. J Lipid Res. (2001)
  345. Fokkema MR, et al. Short-term supplementation of low-dose gamma-linolenic acid (GLA), alpha-linolenic acid (ALA), or GLA plus ALA does not augment LCP omega 3 status of Dutch vegans to an appreciable extent. Prostaglandins Leukot Essent Fatty Acids. (2000)
  346. Emken EA, Adlof RO, Gulley RM. Dietary linoleic acid influences desaturation and acylation of deuterium-labeled linoleic and linolenic acids in young adult males. Biochim Biophys Acta. (1994)
  347. Protein and Amino Acid Requirements in Human Nutrition, page 245, table 49.
  348. Jenkins TA, et al. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. (2016)
  349. Cowen PJ, Browning M. What has serotonin to do with depression?. World Psychiatry. (2015)
  350. Feder A, et al. Tryptophan depletion and emotional processing in healthy volunteers at high risk for depression. Biol Psychiatry. (2011)
  351. Richard DM, et al. L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications. Int J Tryptophan Res. (2009)
  352. Young SN, Leyton M. The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol Biochem Behav. (2002)
  353. Lindseth G, Helland B, Caspers J. The effects of dietary tryptophan on affective disorders. Arch Psychiatr Nurs. (2015)
  354. Kroes MC, et al. Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism. Neuroimage. (2014)
  355. Møller SE, Kirk L, Honoré P. Relationship between plasma ratio of tryptophan to competing amino acids and the response to L-tryptophan treatment in endogenously depressed patients. J Affect Disord. (1980)
  356. Travison TG, et al. The relationship between libido and testosterone levels in aging men. J Clin Endocrinol Metab. (2006)
  357. Chrysohoou C, et al. Low total testosterone levels are associated with the metabolic syndrome in elderly men: the role of body weight, lipids, insulin resistance, and inflammation; the Ikaria study. Rev Diabet Stud. (2013)
  358. Westley CJ, Amdur RL, Irwig MS. High Rates of Depression and Depressive Symptoms among Men Referred for Borderline Testosterone Levels. J Sex Med. (2015)
  359. Giltay EJ, et al. Salivary testosterone: associations with depression, anxiety disorders, and antidepressant use in a large cohort study. J Psychosom Res. (2012)
  360. Feldman HA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. (2002)
  361. Wu FC, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab. (2008)
  362. Handelsman DJ, et al. Age-specific population centiles for androgen status in men. Eur J Endocrinol. (2015)
  363. Cote KA, et al. Sleep deprivation lowers reactive aggression and testosterone in men. Biol Psychol. (2013)
  364. Leproult R, Van Cauter E. Effect of 1 week of sleep restriction on testosterone levels in young healthy men. JAMA. (2011)
  365. Penev PD. Association between sleep and morning testosterone levels in older men. Sleep. (2007)
  366. González-Santos MR, et al. Sleep deprivation and adaptive hormonal responses of healthy men. Arch Androl. (1989)
  367. Cortés-Gallegos V, et al. Sleep deprivation reduces circulating androgens in healthy men. Arch Androl. (1983)
  368. Nedeltcheva AV, et al. Insufficient sleep undermines dietary efforts to reduce adiposity. Ann Intern Med. (2010)
  369. O'Leary CB, Hackney AC. Acute and chronic effects of resistance exercise on the testosterone and cortisol responses in obese males: a systematic review. Physiol Res. (2014)
  370. Kraemer WJ, Ratamess NA. Hormonal responses and adaptations to resistance exercise and training. Sports Med. (2005)
  371. Daly W, et al. Relationship between stress hormones and testosterone with prolonged endurance exercise. Eur J Appl Physiol. (2005)
  372. Hackney AC, Aggon E. Chronic Low Testosterone Levels in Endurance Trained Men: The Exercise- Hypogonadal Male Condition. J Biochem Physiol. (2018)
  373. Grossmann M. Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. (2011)
  374. Tajar A, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. (2010)
  375. Hall SA, et al. Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample. J Clin Endocrinol Metab. (2008)
  376. Grossmann M, Matsumoto AM. A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management. J Clin Endocrinol Metab. (2017)
  377. Corona G, et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol. (2013)
  378. Camacho EM, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol. (2013)
  379. Pilz S, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res. (2011)
  380. Wehr E, et al. Association of vitamin D status with serum androgen levels in men. Clin Endocrinol (Oxf). (2010)
  381. Uwitonze AM, Razzaque MS. Role of Magnesium in Vitamin D Activation and Function. J Am Osteopath Assoc. (2018)
  382. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride.
  383. Gonzales-Arimborgo C, et al. Acceptability, Safety, and Efficacy of Oral Administration of Extracts of Black or Red Maca (Lepidium meyenii) in Adult Human Subjects: A Randomized, Double-Blind, Placebo-Controlled Study. Pharmaceuticals (Basel). (2016)
  384. Zenico T, et al. Subjective effects of Lepidium meyenii (Maca) extract on well-being and sexual performances in patients with mild erectile dysfunction: a randomised, double-blind clinical trial. Andrologia. (2009)
  385. Gonzales GF, et al. Effect of Lepidium meyenii (MACA) on sexual desire and its absent relationship with serum testosterone levels in adult healthy men. Andrologia. (2002)
  386. Dording CM, et al. A double-blind placebo-controlled trial of maca root as treatment for antidepressant-induced sexual dysfunction in women. Evid Based Complement Alternat Med. (2015)
  387. G. D’Aniello, et al. D-asparate, a key element for the improvement of sperm quality. Advances in Sexual Medicine. (2012)
  388. Topo E, et al. The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. Reprod Biol Endocrinol. (2009)
  389. Melville GW, Siegler JC, Marshall PW. Three and six grams supplementation of d-aspartic acid in resistance trained men. J Int Soc Sports Nutr. (2015)
  390. Willoughby DS, Leutholtz B. D-aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men. Nutr Res. (2013)